Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity

ABSTRACT

The present invention is to provide a novel compound (I) shown below, having the anti-virus activity, particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. 
     
       
         
         
             
             
         
       
     
     (wherein
         Z 1  is NR 4 ;   R 1  is hydrogen or lower alkyl;   X is a single bond, a hetero atom group selected from O, S, SO, SO 2  and NH, or lower alkylene or lower alkenylene in which the hetero atom group may intervene;   R 2  is optionally substituted aryl;   R 3  is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and   R 4  and Z 2  part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.

TECHNICAL FIELD

The present invention relates to novel compounds possessing an antiviralactivity, in detail polycyclic carbamoylpyridone derivatives possessingan inhibitory activity against HIV integrase and a pharmaceuticalcomposition containing the same, especially an anti-HIV agent.

BACKGROUND ART

Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus,is known to cause acquired immunodeficiency syndrome (AIDS). Thetherapeutic agent for AIDS is mainly selected from a group of reversetranscriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g.,Indinavir), but they are proved to be accompanied by side effects suchas nephropathy and the emergence of resistant viruses. Thus, thedevelopment of anti-HIV agents having the other mechanism of action hasbeen desired.

On the other hand; a combination therapy is reported to be efficient intreatment for AIDS because of the frequent emergence of the resistantmutant. Reverse transcriptase inhibitors and protease inhibitors areclinically used as an anti-HIV agent, however agents having the samemechanism of action often exhibit cross-resistance or only an additionalactivity. Therefore, anti-HIV agents having the other mechanism ofaction are desired.

Under the circumstances above, an HIV integrase inhibitor has beenfocused on as an anti-HIV agent having a novel mechanism of action (Ref:Patent Documents 1 and 2). As an anti-HIV agent having such a mechanismof action, known are carbamoyl-substituted hydroxypyrimidinonederivative (Ref: Patent Documents 3 and 4) and carbamoyl-substitutedhydroxypyrrolidione derivative (Ref: Patent Document 5). Further, apatent application concerning carbamoyl-substituted hydroxypyridonederivative has been filed (Ref: Patent Document 6, Example 8).

Other known carbamoylpyridone derivatives include5-alkoxypyridine-3-carboxamide derivatives and r-pyrone-3-carboxamidederivatives, which are a plant growth inhibitor or herbicide (Ref PatentDocuments 7-9).

Other HIV integrase inhibitors include N-containing condensed cycliccompounds (Ref: Patent Document 10).

[Patent Document 1] WO003/0166275 [Patent Document 2] WO2004/024698[Patent Document 3] WO03/035076 [Patent Document 4] WO03/035076 [PatentDocument 5] WO2004/004657 [Patent Document 6] JP Patent Application2003-32772 [Patent Document 7] JP Patent Publication 1990-108668 [PatentDocument 8] JP Patent Publication 1990-108688 [Patent Document 9] JPPatent Publication 1990-96506 [Patent Document 10] WO2005/016927DISCLOSURE OF INVENTION Problem to be Solved by the Invention

The development of a novel integrase inhibitor has been desired.

Means to Solve the Problem

The present inventors have intensively studied to find that a novelpolycyclic carbamoylpyridone derivative possesses a potent HIV integraseinhibitory activity.

Moreover, the present inventors have discovered that a compound of thepresent invention and a pharmaceutical composition containing the sameare useful as an antiviral agent, an antiretroviral agent, an anti-HIVagent, an anti-HTLV-1 (Human T cell leukemia virus type 1) agent, ananti-FIV (Feline immunodeficiency virus) agent or an anti-SIV (Simianimmunodeficiency virus) agent, especially an anti-HIV agent or anti-AIDSagent, to accomplish the present invention shown below.

(1) A compound of the formula:

(wherein,

Z¹ is NR⁴;

R⁴ is hydrogen, optionally substituted lower alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkyl lower alkyl,optionally substituted lower alkenyl, optionally substituted loweralkoxy, optionally substituted aryl, optionally substituted aryl loweralkyl, optionally substituted aryloxy, optionally substitutedheterocyclic group, optionally substituted heterocycle lower alkyl,optionally substituted heterocycleoxy, hydroxy, optionally substitutedamino, optionally substituted phosphoric acid residue, aryl substitutedwith optionally substituted phosphoric acid residue, aralkyl substitutedwith optionally substituted phosphoric acid residue, hydroxy substitutedwith optionally substituted phosphoric acid residue, amino substitutedwith optionally substituted phosphoric acid residue or lower alkylsubstituted with optionally substituted phosphoric acid residue (thelower alkyl may be intervened by a heteroatom group selected from CO, O,S, SO, SO₂, NR^(a) (R^(a) is hydrogen or lower alkyl), —N═ and ═N—)), Oor CH₂;

Z² is optionally substituted lower alkylene or optionally substitutedlower alkenylene, each may be intervened by a heteroatom group selectedfrom O, S, SO, SO₂, NR⁵ (R⁵ is hydrogen, optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkyl lower alkyl, optionally substituted lower alkenyl, optionallysubstituted lower alkoxy, optionally substituted aryl, optionallysubstituted aryl lower alkyl, optionally substituted aryloxy, optionallysubstituted heterocyclic group, optionally substituted heterocycle loweralkyl, optionally substituted heterocycleoxy, hydroxy or optionallysubstituted amino, optionally substituted phosphoric acid residue, arylsubstituted with optionally substituted phosphoric acid residue, aralkylsubstituted with optionally substituted phosphoric acid residue, hydroxysubstituted with optionally substituted phosphoric acid residue, aminosubstituted with optionally substituted phosphoric acid residue or loweralkyl substituted with optionally substituted phosphoric acid residue(the lower alkyl may be intervened by a heteroatom group selected fromCO, O, S, SO, SO₂, NR⁵ (R⁵ is selected independently from the samesubstituent group as R⁴), —N═ and ═N—)), —N═ or ═N—

R¹ is hydrogen or lower alkyl;

X is a single bond, a heteroatom group selected from O, S, SO, SO₂ andNH, or lower alkylene or lower alkenylene each may be intervened by theheteroatom;

R² is optionally substituted aryl;

R³ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted lower alkenyl,optionally substituted lower alkoxy, optionally substituted loweralkenyloxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heterocyclic group, optionally substitutedheterocycleoxy or optionally substituted amino;

R⁴ and Z² part taken together forms a ring, where the compound (I) isrepresented by the following formula (I-1), or (I-11):

(wherein,

A ring is optionally substituted heterocycle;

R¹⁴ and R^(X) are independently hydrogen, optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkyl lower alkyl, optionally substituted lower alkenyl, optionallysubstituted lower alkoxy, optionally substituted lower alkenyloxy,optionally substituted aryl, optionally substituted aryl lower alkyl,optionally substituted aryloxy, optionally substituted heterocyclicgroup, optionally substituted heterocycle lower alkyl, optionallysubstituted heterocycleoxy, optionally substituted phosphoric acidresidue, aryl substituted with optionally substituted phosphoric acidresidue, aralkyl substituted with optionally substituted phosphoric acidresidue, hydroxy substituted with optionally substituted phosphoric acidresidue, amino substituted with optionally substituted phosphoric acidresidue or lower alkyl substituted with optionally substitutedphosphoric acid residue (the lower alkyl may be intervened by aheteroatom group selected from O, S, SO, SO₂, NR⁵ (R⁵ is selectedindependently from the same substituent group as R⁴), —N═ and ═N—),hydroxy, optionally substituted amino, optionally substituted loweralkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionallysubstituted cycloalkyl lower alkyl carbonyl, optionally substitutedlower alkoxy carbonyl, optionally substituted arylcarbonyl, optionallysubstituted aryl lower alkyl carbonyl, optionally substitutedaryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionallysubstituted heterocycle lower alkyl carbonyl, optionally substitutedheterocycleoxy carbonyl or optionally substituted aminocarbonyl;

a broken line represents the presence or absence of a bond, providedthat when the broken line represents the presence of a bond, R^(x) isnot present;

R¹ is hydrogen or lower alkyl;

X is a single bond, a heteroatom group selected from O, S, SO, SO₂ and NH, or lower alkylene or lower alkenylene each may be intervened by theheteroatom group;

R² is optionally substituted aryl;

R³ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted lower alkenyl,optionally substituted lower alkoxy, optionally substituted loweralkenyloxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heterocyclic group, optionally substitutedheterocycleoxy or optionally substituted amino)

(wherein,

D ring is optionally substituted heterocycle;

R¹ is hydrogen or lower alkyl;

X is a single bond, a heteroatom group selected from O, S, SO, SO₂ andNH, or lower alkylene or lower alkenylene each may be intervened by theheteroatom group;

R² is optionally substituted aryl;

R³ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted lower alkenyl,optionally substituted lower alkoxy, optionally substituted loweralkenyloxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heterocyclic group, optionally substitutedheterocycleoxy or optionally substituted amino)), its pharmaceuticallyacceptable salt, or solvate thereof.

(2) A compound according to the above (1), pharmaceutically acceptablesalt, or solvate thereof, wherein R¹ is hydrogen.(3) A compound according to the above (1), pharmaceutically acceptablesalt, or solvate thereof, wherein X is lower alkylene; R² is phenyl orphenyl substituted with at least halogen.(4) A compound according to the above (1), pharmaceutically acceptablesalt, or solvate thereof, wherein R³ is hydrogen, halogen, hydroxy,lower alkyl, lower alkenyl, lower alkoxy, lower alkenyloxy or optionallysubstituted amino.(5) A compound according to the above (1), pharmaceutically acceptablesalt, or solvate thereof, wherein R³ is hydrogen.(6) A compound according to the above (1), pharmaceutically acceptablesalt, or solvate thereof, wherein R¹ is hydrogen or lower alkyl; X islower alkylene; R² is phenyl or phenyl substituted with at leasthalogen; R³ is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl,lower alkoxy, lower alkenyloxy or optionally substituted amino.(7) A compound of the formula:

(wherein,

A ring is optionally substituted heterocycle;

R¹⁴ and R^(X) are independently hydrogen, optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkyl lower alkyl, optionally substituted lower alkenyl, optionallysubstituted lower alkoxy, optionally substituted lower alkenyloxy,optionally substituted aryl, optionally substituted aryl lower alkyl,optionally substituted aryloxy, optionally substituted heterocyclicgroup, optionally substituted heterocycle lower alkyl, optionallysubstituted heterocycleoxy, optionally substituted phosphoric acidresidue, aryl substituted with optionally substituted phosphoric acidresidue, aralkyl substituted with optionally substituted phosphoric acidresidue, hydroxy substituted with optionally substituted phosphoric acidresidue, amino substituted with optionally substituted phosphoric acidresidue or lower alkyl substituted with optionally substitutedphosphoric acid residue (the lower alkyl may be intervened by aheteroatom group selected from O, S, SO, SO₂, NR⁵ (R⁵ is selectedindependently from the same substituent group as R⁴), —N═ and ═N—),hydroxy, optionally substituted amino, optionally substituted loweralkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionallysubstituted cycloalkyl lower alkyl carbonyl, optionally substitutedlower alkoxy carbonyl, optionally substituted arylcarbonyl, optionallysubstituted aryl lower alkyl carbonyl, optionally substitutedaryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionallysubstituted heterocycle lower alkyl carbonyl, optionally substitutedheterocycleoxy carbonyl or optionally substituted aminocarbonyl;

a broken line represents the presence or absence of a bond, providedthat when the broken line represents the presence of a bond, R^(x) isnot present;

R¹ is hydrogen or lower alkyl;

X is a single bond, a heteroatom group selected from O, S, SO, SO₂ andNH, or lower alkylene or lower alkenylene each may be intervened by theheteroatom group;

R² is optionally substituted aryl;

R³ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted lower alkenyl,optionally substituted lower alkoxy, optionally substituted loweralkenyloxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heterocyclic group, optionally substitutedheterocycleoxy or optionally substituted amino), its pharmaceuticallyacceptable salt, or solvate thereof

(8) A compound according to the above (7), pharmaceutically acceptablesalt, or solvate thereof, wherein R¹ is hydrogen or lower alkyl; X islower alkylene; R² is phenyl or phenyl substituted with at leasthalogen; R³ is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl,lower alkoxy, lower alkenyloxy or optionally substituted amino.(9) A compound according to the above (7), pharmaceutically acceptablesalt, or solvate thereof, wherein a broken line represents the absenceof a bond.(10) A compound according to the above (7), pharmaceutically acceptablesalt, or solvate thereof, wherein R^(X) is hydrogen; R¹⁴ is hydrogen oroptionally substituted lower alkyl.(11) A compound according to the above (7), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is an optionally substitutedand optionally condensed 5- to 7-membered heterocycle containing 1 to 2hetero atom(s).(12) A compound of the formula:

(wherein,

A ring is an optionally substituted and optionally condensed 5- to7-membered heterocycle containing 1 to 2 hetero atom(s);

the stereochemistry of an asymmetric carbon represented by * shows R- orS-configuration, or a mixture thereof;

R¹⁴ and R^(X) are independently hydrogen, optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkyl lower alkyl, optionally substituted lower alkenyl, optionallysubstituted lower alkoxy, optionally substituted lower alkenyloxy,optionally substituted aryl, optionally substituted aryl lower alkyl,optionally substituted aryloxy, optionally substituted heterocyclicgroup, optionally substituted heterocycle lower alkyl, optionallysubstituted heterocycleoxy, optionally substituted phosphoric acidresidue, aryl substituted with optionally substituted phosphoric acidresidue, aralkyl substituted with optionally substituted phosphoric acidresidue, hydroxy substituted with optionally substituted phosphoric acidresidue, amino substituted with optionally substituted phosphoric acidresidue or lower alkyl substituted with optionally substitutedphosphoric acid residue (the lower alkyl may be intervened by aheteroatom group selected from O, S, SO, SO₂, NR⁵ (R⁵ is selectedindependently from the same substituent group as R⁴), —N═ and ═N—),hydroxy, optionally substituted amino, optionally substituted loweralkyl carbonyl, optionally substituted cycloalkylcarbonyl, optionallysubstituted cycloalkyl lower alkyl carbonyl, optionally substitutedlower alkoxy carbonyl, optionally substituted arylcarbonyl, optionallysubstituted aryl lower alkyl carbonyl, optionally substitutedaryloxycarbonyl, optionally substituted heterocyclecarbonyl, optionallysubstituted heterocycle lower alkyl carbonyl, optionally substitutedheterocycleoxy carbonyl or optionally substituted aminocarbonyl;

R³ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted lower alkenyl,optionally substituted lower alkoxy, optionally substituted loweralkenyloxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heterocyclic group, optionally substitutedheterocycleoxy or optionally substituted amino), its pharmaceuticallyacceptable salt, or

R¹ is hydrogen or lower alkyl;

R is independently selected from halogen and Substituent group S1;

Substituent group S1 (: optionally substituted phosphoric acid residue,aryl substituted with optionally substituted phosphoric acid residue,aralkyl substituted with optionally substituted phosphoric acid residue,hydroxy substituted with optionally substituted phosphoric acid residue,amino substituted with optionally substituted phosphoric acid residue,or lower alkyl substituted with optionally substituted phosphoric acidresidue (wherein the lower alkyl may be intervened with a heteroatomgroup(s) selected from CO, O, O, S, SO, SO₂, NR^(a) (R^(a) is hydrogenor lower alkyl), —N═ and ═N—), lower alkoxy lower alkyl, amino loweralkyl optionally substituted with mono- or di-lower alkyl, halogenatedlower alkyl, lower alkoxy, carbamoyl optionally substituted with mono-or di-lower alkyl, optionally substituted lower alkyl sulfonyl amino,halogenated lower alkoxy, hydroxy lower alkyl)

m is an integer of 0 to 3, its pharmaceutically acceptable salt, orsolvate thereof.

(13) A compound according to the above (12), pharmaceutically acceptablesalt, or solvate thereof, wherein R^(X) and R¹⁴ are independentlyhydrogen or optionally substituted lower.(14) A compound according to the above (12), pharmaceutically acceptablesalt, or solvate thereof, wherein R^(X) and R¹⁴ are hydrogens.(15) A compound according to the above (12), pharmaceutically acceptablesalt, or solvate thereof, wherein R³ is hydrogen.(16) A compound according to the above (12), pharmaceutically acceptablesalt, or solvate thereof, wherein m is 0, or 1 to 3 and at least one ofR is halogen.(17) A compound according to the above (7) or (12), pharmaceuticallyacceptable salt, or solvate thereof, wherein A ring is any one of thefollowing:

-   (wherein, R²⁰ to R⁴⁰ are each independently a group selected from    Substituent group S2, or any two groups of R²⁰ to R⁴⁰, which bonds    to the same carbon atom, taken together with the carbon atom, may    form an optionally substituted carbocycle or optionally substituted    heterocycle, or each combination of (R²⁰ and R²²), (R²³ and R²⁴),    (R²⁵ and R²⁶), (R²⁷ and R²⁹), (R³⁰ and R³¹), (R³² and R³⁴), (R³⁵ and    R³⁶), (R³⁷ and R³⁸), and (R³⁹ and R⁴⁰), taken together with the    neighboring atom, may form an optionally substituted carbocycle or    optionally substituted heterocycle.    Substituent group S2: hydrogen, optionally substituted lower alkyl,    optionally substituted cycloalkyl, optionally substituted cycloalkyl    lower alkyl, optionally substituted lower alkenyl, optionally    substituted lower alkoxy, optionally substituted lower alkenyloxy,    optionally substituted aryl, optionally substituted aryl lower    alkyl, optionally substituted aryloxy, optionally substituted    heterocycle, optionally substituted heterocycle lower alkyl,    optionally substituted heterocycleoxy, hydroxy, optionally    substituted amino, optionally substituted lower alkylcarbonyl,    optionally substituted cycloalkylcarbonyl, optionally substituted    cycloalkyl lower alkylcarbonyl, optionally substituted lower    alkoxycarbonyl, optionally substituted arylcarbonyl, optionally    substituted aryl lower alkylcarbonyl, optionally substituted aryl    oxycarbonyl, optionally substituted heterocyclecarbonyl, optionally    substituted heterocycle lower alkylcarbonyl, optionally substituted    heterocycleoxycarbonyl, optionally substituted aminocarbonyl,    optionally substituted phosphoric acid residue, aryl substituted    with optionally substituted phosphoric acid residue, aralkyl    substituted with optionally substituted phosphoric acid residue,    hydroxy substituted with optionally substituted phosphoric acid    residue, amino substituted with optionally substituted phosphoric    acid residue, or lower alkyl substituted with optionally substituted    phosphoric acid residue (the lower alkyl may be intervened with a    heteroatom group(s) selected from CO, O, S, SO, SO₂, NR⁵ (R⁵ is    independently selected from the same Substituent group as R⁴), —N═    and ═N—)

the stereochemistry of an asymmetric carbon represented by * shows R- orS-configuration, or a mixture thereof)

(18) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein R²⁰ to R⁴⁰ are each independentlyhydrogen or substituted lower alkyl, or any two groups of R²⁰ to R⁴⁰,which bonds to the same carbon atom, taken together with the carbonatom, may form an optionally substituted 3- to 7-membered carbocycle oroptionally substituted 3- to 7-membered heterocycle, or each combinationof (R²⁰ and R²²), (R²³ and R²⁴), (R²⁵ and R²⁶), (R²⁷ and R²⁹), (R³⁰ andR³¹), (R³² and R³⁴), (R³⁵ and R³⁶), (R³⁷ and R³⁸), and (R³⁹ and R⁴⁰),taken together with the neighboring atom, may form an optionallysubstituted 5- to 7-membered carbocycle or optionally substituted 5- to7-membered heterocycle.(19) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-1);one of R²⁰ to R²⁵ is optionally substituted lower alkyl and the othersare hydrogens.(20) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-1);one of (R²⁰ and R²²), (R²³ and R²⁴), and (R²⁵ and R²⁶), taken togetherwith the neighboring atom, may form an optionally substituted 5- to7-membered carbocycle or optionally substituted 5- to 7-memberedheterocycle.(21) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-1);Z═NR²⁶, and R²⁵ and R²⁶ taken together with the neighboring atom mayform an optionally substituted 5- to 7-membered heterocycle.(22) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-2);one of R²⁷ to R³⁰ is optionally substituted lower alkyl and the othersare hydrogens.(23) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-2);one of (R²⁷ and R²⁹) and (R³⁰ and R³¹), taken together with theneighboring atom, may form an optionally substituted 5- to 7-memberedcarbocycle or optionally substituted 5- to 7-membered heterocycle.(24) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-2);Z═NR³¹, and R³⁰ and R³¹ taken together with the neighboring atom mayform an optionally substituted 5- to 7-membered heterocycle.(25) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-3);one of R³² to R³⁹ is optionally substituted lower alkyl and the othersare hydrogens.(26) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-3);one of (R³² and R³⁴), (R³⁵ and R³⁶), (R³⁷ and R³⁸), and (R³⁹ and R⁴⁰),taken together with the neighboring atom, may form an optionallysubstituted 5- to 7-membered carbocycle or optionally substituted 5- to7-membered heterocycle.(27) A compound according to the above (17), pharmaceutically acceptablesalt, or solvate thereof, wherein A ring is a ring represented by (A-3);Z═NR⁴⁰, and R³⁹ and R⁴⁰ taken together with the neighboring atom mayform an optionally substituted 5- to 7-membered heterocycle.(28) A compound according to the above (12), pharmaceutically acceptablesalt, or solvate thereof, wherein R^(X) is hydrogen; R¹⁴ is hydrogen oroptionally substituted lower; R³ is hydrogen; m is 1 to 3 and at leastone of Rs is halogen; A ring is a ring described in Claim 17.(29) A compound according to the above (12), pharmaceutically acceptablesalt, or solvate thereof, wherein R^(X) is hydrogen; R¹⁴ is hydrogen; R³is hydrogen; m is 0, or 1 to 3 and at least one of Rs is halogen; A ringis a ring described in Claim 17; R²⁰ to R⁴⁰ are each independentlyhydrogen or substituted lower alkyl, or any two groups of R²⁰ to R⁴⁰,which bonds to the same carbon atom, taken together with the carbonatom, may form an optionally substituted 3- to 7-membered carbocycle oroptionally substituted 3- to 7-membered heterocycle, or each combinationof (R²⁰ and R²²), (R²³ and R²⁴), (R²⁵ and R²⁶), (R²⁷ and R²⁹), (R³⁰ andR³¹), (R³² and R³⁴), (R³⁵ and R³⁶), (R³⁷ and R³⁸), and (R³⁹ and R⁴⁰),taken together with the neighboring carbon atom, may form an optionallysubstituted 5- to 7-membered carbocycle or optionally substituted 5- to7-membered heterocycle.(30) A compound of the formula:

(wherein,

D ring is optionally substituted heterocycle;

R¹ is hydrogen or lower alkyl;

X is a single bond, a heteroatom group selected from O, S, SO, SO₂ andNH, or lower alkylene or lower alkenylene each may be intervened by theheteroatom group;

R² is optionally substituted aryl;

R³ is hydrogen, halogen, hydroxy, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted lower alkenyl,optionally substituted lower alkoxy, optionally substituted loweralkenyloxy, optionally substituted aryl, optionally substituted aryloxy,optionally substituted heterocyclic group, optionally substitutedheterocycleoxy or optionally substituted amino), pharmaceuticallyacceptable salt, or solvate thereof

(31) A compound selected from the group consisting of:

-   (3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (4aR,13aS)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide;-   (3aS,13aS)—N-[(2,4-Difluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide;-   (4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide;-   (4aS,13aR)—N-[(4-Fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3aS,13aS)—N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1S)-1-methylpropyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(hydroxymethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-phenyl-2,3,6,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(2-methylpropyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (5aR,14aR)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide;-   (2S,3S)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(methyloxy)methyl]-5,7-dioxo-2-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)-3-(Cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (5aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-5a,6a,7,11,13,14a-hexahydro-5H-indeno[1′,2′:4,5][1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-10-carboxamide;-   (2S,3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (2S,3R,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylsulfonyl)ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1H-indol-3-ylmethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4R,12aR)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(1,3-thiazol-2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide;-   (4aR,6aR,14aR)—N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,    4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide;-   (3S,4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-3-phenyl-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide;-   (4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-methylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazolino-10-carboxamide;-   (6aR,7aS,11aS)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide;-   (6aS,7aS,11aS)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide;-   (5aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide;-   (4aR,14aR)—N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide;-   (4R,12aR)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(3-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)-1-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (3aS,5aS,13aS)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-5-(2-methylpropyl)-10,12-dioxo-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide,-   (3aR,5aR,13aS)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide;-   (4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-methyl-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;-   (4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(methyloxy)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;-   (4aS,6aS,14aS)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)-3-Butyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-a]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(4-hydroxyphenyl)methyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (4S,12aS)-1-Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidino-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-hydroxyethyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;-   (4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;-   (4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-6-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide;-   (4aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide;-   (4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)-1-Cyclobutyl-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(4-Fluorophenyl)methyl]-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;    enantiomers thereof; diastereomers thereof; mixtures of enantiomers    thereof; mixtures of diastereomers thereof, mixtures of enantiomers    and diastereomers thereof; and pharmaceutically acceptable salts    thereof.

(32) A compound selected from the group consisting of:

-   (4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrazine-8-carboxamide;-   (4aS,13aR)—N-[(4-Fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1S)-1-methylpropyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (3S,11aR)—N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide;-   (4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide;-   (4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2a]pyrimidine-9-carboxamide;-   (4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide;-   (4a,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide;-   4S,9aR)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic    acid 2,4,-difluoro-benzylamide;-   4R,9aS)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic    acid 2,4,-difluoro-benzylamide;-   2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic    acid 4-fluoro-benzylamide;    enantiomers thereof; diastereomers thereof; mixtures of enantiomers    thereof; mixtures of diastereomers thereof; mixtures of enantiomers    and diastereomers thereof; and pharmaceutically acceptable salts    thereof.    (33) A compound according to the above (31) or (32) wherein the    pharmaceutically acceptable salt is a sodium salt.    (34) A pharmaceutical composition comprising a compound according to    any one of the above (1) to (33), or a pharmaceutically acceptable    salt, or solvate thereof.    (35) A pharmaceutical composition according to the above (34), which    is an anti-HIV agent.    (36) A process for the preparation of a compound of formula (I-20a)

wherein R^(e) is one or two halogen; R^(z) is C₁₋₈alkyl,C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryl, or alkoxy; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a compound of the formula

wherein R^(z) is C₁₋₈alkyl, C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryl, or alkoxy;to form a compound of formula (I-20a).(37) A process for the preparation of a compound of formula (I-20b)

wherein R^(e) is one or two halogen; R^(z) is C₁₋₈alkyl,C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryl, or alkoxy; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl; with a compound of the formula

wherein R^(x) is C₁₋₈alkyl, C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryl, or alkoxy;to form a compound of formula (I-20b).(38) A process for the preparation of a compound of formula (I-21a)

wherein R^(e) is one or two halogen; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a compound of the formula

to form a compound of formula (I-21a).(39) A process for the preparation of a compound of formula (I-21b)

wherein R^(e) is one or two halogen; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a compound of the formula

to form a compound of formula (I-21b).(40) A process for the preparation of a compound of formula (I-22a)

wherein R^(e) is one or two halogen; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a compound of the formula

to form a compound of formula (I-22a),(41) A process for the preparation of a compound of formula (I-22b)

wherein R^(e) is one or two halogen; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a compound of the formula

to form a compound of formula (I-22b).(42) A process for the preparation of a compound of formula (I-23a)

wherein R^(e) is one or two halogen; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a compound of the formula

to form a compound of formula (I-23a).(43) A process for the preparation of a compound of formula (I-23b)

wherein R^(e) is one or two halogen; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl;with a compound of the formula

to form a compound of formula (I-23b).(44) A process for the preparation of a compound of formula (I-24a)

wherein R^(e) is one or two halogen; R^(z) is C₁₋₈alkyl; R^(z1) ishydrogen, C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyl optionallysubstituted with hydroxy, C₃₋₆cycloalkyl, alkoxy, heterocycle,heteroaryl, C₆₋₁₄aryl, or amino, wherein said amino may be optionallysubstituted with —C(O)C₁₋₈alkyl or C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; and R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a compound of the formula

wherein R^(z) is C₁₋₈alkyl; R^(z1) is hydrogen, C₃₋₆cycloalkyl,heterocycle, or C₁₋₈alkyl optionally substituted with hydroxy,C₃₋₆cycloalkyl, alkoxy, heterocycle, heteroaryl, C₆₋₁₄aryl, or amino,wherein said amino may be optionally substituted with —C(O)C₁₋₈alkyl orC₁₋₈alkyl;to form a compound of the formula (I-24a).(45) A process for the preparation of a compound of formula (I-24b)

wherein R^(e) is one or two halogen; R^(z) is C₁₋₈alkyl; R^(z1) ishydrogen, C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyl optionallysubstituted with hydroxy, C₃₋₆cycloalkyl, alkoxy, heterocycle,heteroaryl, C₁₋₈aryl, or amino, wherein said amino may be optionallysubstituted with —C(O)C₆₋₁₄alkyl or C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a compound of the formula

wherein R^(z) is C₁₋₈alkyl; and R^(z1) is hydrogen, C₃₋₆cycloalkyl,heterocycle, or C₁₋₈alkyl optionally substituted with hydroxy,C₃₋₆cycloalkyl, alkoxy, heterocycle, heteroaryl, C₆₋₁₄aryl, or amino,wherein said amino may be optionally substituted with —C(O)C₁₋₈alkyl orC₁₋₈alkyl;to form a compound of the formula (I-24b).(46) A process for the preparation of a racemic compound of formula(I-25)

wherein R^(e) is one or two halogen; R^(z1) is hydrogen, C₃₋₆cycloalkyl,heterocycle, or C₁₋₈alkyl optionally substituted with hydroxy,C₃₋₆cycloalkyl, alkoxy, heterocycle, heteroaryl, C₆₋₁₄aryl, or amino,wherein said amino may be optionally substituted with —C(O)C₁₋₈alkyl orC₁₋₈alkyl; and P¹ is is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; and R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;with a racemic compound of the formula

wherein R^(z1) is hydrogen, C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyloptionally substituted with hydroxy, C₃₋₆cycloalkyl, alkoxy,heterocycle, heteroaryl, C₆₋₁₄aryl, or amino, wherein said amino may beoptionally substituted with —C(O)C₁₋₈alkyl or C₁₋₈alkyl;to form a racemic compound of the formula (I-25).(47) A process for the preparation of a racemic compound of formula(I-26)

wherein R^(e) is one or two halogen; R^(z1) is hydrogen, C₃₋₆cycloalkyl,heterocycle, or C₁₋₈alkyl optionally substituted with hydroxy,C₃₋₆cycloalkyl, alkoxy, heterocycle, heteroaryl, C₆₋₁₄aryl, or amino,wherein said amino may be optionally substituted with —C(O)C₁₋₈alkyl orC₁₋₈alkyl; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl; with a racemic compound of the formula

wherein R^(e) is hydrogen, C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyloptionally substituted with hydroxy, C₃₋₆cycloalkyl, alkoxy,heterocycle, heteroaryl, C₆₋₁₄aryl, or amino, wherein said amino may beoptionally substituted with —C(O)C₁₋₈alkyl or C₁₋₈alkyl;to form a racemic compound of formula (I-26).(48) A process for the preparation of a racemic compound of formula(I-27)

wherein R^(e) is halogen; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;comprising condensing a compound of the formula

wherein R^(e) is one or two halogen; R⁵⁰ is C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl; with a racemic compound of the formula

to form a racemic compound of formula (I-27).(49). A compound of formula (I-20a) described in above (36). formula(I-20b) described in above (37), formula (I-21a) described in above(38), formula (I-21b) described in above (39), formula (I-22a) describedin above (40), formula (I-22b) described in above (41), formula (I-23a)described in above (42), formula (I-23b) described in above (43),formula (I-24a) described in above (44), formula (I-24b) described inabove (45), formula (I-25) described in above (46), formula (I-26)described in above (47), or formula (I-27) described in above (48), or apharmaceutically acceptable salt thereof.(50) A compound of formula (I-20a) described in above (36). formula(I-20b) described in above (37), formula (I-21a) described in above(38), formula (I-21b) described in above (39), formula (I-22a) describedin above (40), formula (I-22b) described in above (41), formula (I-23a)described in above (42), formula (I-23b) described in above (43),formula (I-24a) described in above (44), formula (I-24b) described inabove (45), formula (I-25) described in above (46), formula (I-26)described in above (47), or formula (I-27) described in above (48), or apharmaceutically acceptable salt thereof, wherein each P¹ is hydrogen.

The present invention further provides a pharmaceutical compositioncontaining any of the compounds shown above, a pharmaceuticallyacceptable salt or a solvate thereof, especially an anti-HIV agent.

Effect of the Invention

The present invention compounds possess an integrase inhibitory activityand/or a cell-growth inhibitory activity against virus, especially HIV.Accordingly, they are useful for the prevention or treatment of variousdiseases mediated by integrase or virus infection diseases (e.g., AIDS).The present invention further provides a process for preparing adiastereomer, a mixture thereof, or racemate.

PREFERRED EMBODIMENT OF THE INVENTION

The terms used herein are explained below. Each term, alone or incombination with another tem, means as follows.

“Lower alkylene” means a straight or branched C1 to C6 alkylene such asmethylene, ethylene, trimethylene, n-propylene, tetramethylene,ethylethylene, pentamethylene, or hexamethylene, preferably C1 to C4straight alkylene such as methylene, ethylene, trimethylene, andtetramethylene, more preferably methylene or ethylene.

“Lower alkenylene” means a straight or branched C2 to C6 alkenylene,which consists of the above “Lower alkylene” having one or more doublebonds, such as vinylene, propylene, or butenylene, preferably a straightC2 to C3 alkenylene such as vinylene or propylene.

“Lower alkyl” moans a straight or branched C1 to C10 alkyl such asmethyl, ethyl, n-propyl, i-propyl, t-butyl, isobutyl, sec-butyl,n-pentyl, and n-hexyl, and preferred is C1 to C3 alkyl, more preferredis methyl, ethyl or n-propyl, n-pentyl, isopentyl, neopentyl,tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, and n-desyl,preferably C1 to C6 lower alkyl, more preferably C1 to C4 lower alkylsuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl,n-hexyl, and isohexyl.

When lower alkyl is intervened with “—N═” or “═N—”, the lower alkyl mayhave a double bond to form —CH₂—N═CH₂, —CH═N—CH₃ etc.

“Alkenyl” means a straight or branched C2 to C8 alkenyl, which consistsof the above “alkyl” having one or more double bonds, such as vinyl,1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl,and 3-methyl-2-butenyl, preferably C2 to C6 alkenyl, and more preferablyC2 to C4 alkenyl.

“Lower alkenyloxy” means oxy attached to the above lower alkenyl, suchas vinyloxy, 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy,3-butenyloxy, 1,3-butadienyloxy, and 3-methyl-2-butenyloxy.

“Cycloalkyl” means C3 to C8 cyclic saturated hydrocarbon, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, andcyclooctyl, preferably C3 to C6 cycloalkyl.

“Cycloalkyl lower alkyl” means lower alkyl substituted with the abovecycloalkyl, such as cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, andcyclohexylethyl, and preferably C3 to C6 cycloalkyl lower alkyl.

“Aryl” means monocyclic aromatic hydrocarbon (e.g., phenyl) andpolycyclic hydrocarbon (e.g., 1-naphthyl, 2-naphthyl, 1-anthryl,2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl,4-phenanthryl, 9-phenanthryl), preferably phenyl or naphthyl (e.g.,1-napthyl, 2-naphthyl).

“Aralkyl” or “aryl lower alkyl” means the above lower alkyl substitutedwith 1 to 3 of the above aryl, such as benzyl, diphenylmethyl,triphenylmethyl, phenethyl, 1-napthylmethyl, 2-napthylmethyl, preferablybenzyl.

“Aryloxy” means oxy attached to the above aryl, such as 1-naphthyloxy,2-naphthyloxy, 1-anthryloxy, 2-anthryloxy, 9-anthryloxy,1-phenanthryloxy, 2-phenanthryloxy, 3-phenanthryloxy, 4-phenanthryloxy,and 9-phenanthryloxy, preferably phenyloxy or naphthyloxy (e.g.,1-napthyloxy, 2-naphthyloxy).

“Heterocyclic group” means “heteroring” or “heteroaryl”.

“Heteroring” means a non-aromatic ring which has at least one of N, Oand/or S in the ring and may be bonded at any substitutable position,preferably 5- to 7-membered ring, such as 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl,4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl,piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl, 1-piperadinyl,2-piperadinyl, 2-morpholinyl, 3-morpholinyl, morpholino, andtetrahydropyranyl. The non-aromatic ring is a saturated or unsaturatedring.

“Heteroaryl” means monocyclic aromatic hetero-type ring or condensedaromatic hetero-type ring.

“Monocyclic aromatic hetero-type ring” means a 5- to 8-membered aromaticring, which contains 1 to 4 of O, S, P and/or N and may be bonded at anysubstitutable position.

“Condensed aromatic hetero-type ring” means a group wherein an aromaticring containing 1 to 4 of O, S, P and/or N is condensed with 1 to 4 of5- to 8-membered aromatic ring(s) or the other 5- to 8-membered aromaticheteroring(s).

Examples of “heteroaryl” include furyl (e.g., 2-furyl, 3-furyl), thienyl(e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl(e.g., 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,4-triazole-4-yl),tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl(e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g.,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (e.g., 2-thiazolyl,4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (e.g.,3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridil (e.g.,2-pyridyl, 3-pyridil, 4-pyridil), pyridazinyl (e.g., 3-pyridazinyl,4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl), furazanyl (e.g., 3-furazanyl), pyrazinyl (e.g.,2-pyrazinyl), oxadiazolyl (e.g., 1,3,4-oxadiazole-2-yl), benzofuryl(e.g., 2-benzo[b]furyl, 3-benzo[b]furyl, 4-benzo[b]furyl,5-benzo[b]furyl, 6-benzo[b]furyl, 7-benzo[b]furyl), benzothienyl (e.g.,2-benzo[b]thienyl, 3-benzo[b]thienyl, 4-benzo[b]thienyl,5-benzo[b]thienyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl),benzoimidazolyl (e.g., 1-benzoimidazolyl, 2-benzoimidazolyl,4-benzoimidazolyl, 5-benzoimidazolyl), dibenzofuryl, benzooxazolyl,quinoxalinyl (e.g., 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl),cinnolinyl (e.g., 3-cinnolinyl, 4-cinnolinyl, 5-cinnolinyl,6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolinyl (e.g.,2-quinazolinyl, 4-quinazolinyl, 5-quinazolinyl, 6-quinazolinyl,7-quinazolinyl, 8-quinazolinyl), quinolyl(e.g., 2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl),phthalazinyl (e.g., 1-phthalazinyl, 5-phthalazinyl, 6-phthalazinyl),isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl,5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), purinyl,pteridinyl (e.g., 2-pteridinyl, 4-pteridinyl, 6-pteridinyl,7-pteridinyl), carbazolyl, phenanthridinyl, acridinyl (e.g.,1-acridinyl, 2-acridinyl, 3-acridinyl, 4-acridinyl, 9-acridinyl),indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl,6-indolyl, 7-indolyl), isoindolyl, phenandinyl (e.g., 1-phenandinyl,2-phenandinyl) or phenothiadinyl (e.g., 1-phenothiadinyl,2-phenothiadinyl, 3-phenothiadinyl, 4-phenothiadinyl).

“Heterocycle” means a cycle which can be lead to the above heterocyclicgroup.

“Heterocyclic group lower alkyl” or “Heterocycle lower alkyl” meanslower alkyl substituted with the above heterocyclic group.

“Heterocyclic group oxy” or “Heterocycle oxy” means an oxy attached tothe above heterocyclic group.

“Heterocyclic group carbonyl” or “Heterocyclecarbonyl” means a carbonylattached to the above heterocyclic group

“Lower alkoxy” or “alkoxy” means an oxy attached to the above loweralkyl, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy.

“Lower alkylcarbonyl”, “cycloalkylcarbonyl”, “cycloalkyl loweralkylcarbonyl”, “lower alkoxycarbonyl”, “arylcarbonyl”, “aryl loweralkylcarbonyl”, “aryloxycarbonyl”, “heterocycle carbonyl”, “heterocyclelower alkylcarbonyl”, and “heterocycle oxycarbonyl”, each means acarbonyl attached to the above “lower alkyl”, “cycloalkyl”, “cycloalkyllower alkyl”, “lower alkoxy”, “aryl”, “aryl lower alkyl”, “aryloxy”,“heterocycle”, “heterocycle lower alkyl”, and “heterocycleoxy”,respectively.

When a substituent(s) is/are present on “optionally substituted loweralkyl”, “optionally substituted cycloalkyl”, “optionally substitutedcycloalkyl lower alkyl”, “optionally substituted lower alkenyl”,“optionally substituted lower alkoxy”, “optionally substituted aryl”,“optionally substituted aryl lower alkyl”, “optionally substitutedaryloxy”, “optionally substituted aryloxy lower alkyl”, “optionallysubstituted heterocyle, “optionally substituted heterocyclic group”,“optionally substituted heterocycle lower alkyl”, “optionallysubstituted heterocycleoxy”, “optionally substituted lower alkenyloxy”.“optionally substituted lower alkylcarbonyl”, “optionally substitutedcycloalkylcarbonyl”, “optionally substituted cycloalkyl loweralkylcarbonyl”, “optionally substituted lower alkoxycarbonyl”,“optionally substituted arylcarbonyl”, “optionally substituted aryllower alkylcarbonyl”, “optionally substituted aryloxycarbonyl”,“optionally substituted heterocyclecarbonyl”, “optionally substitutedheterocycle lower alkylcarbonyl”, “optionally substitutedheterocycleoxycarbonyl”, “optionally substituted lower alkylene”,“optionally substituted lower alkenylene”, “optionally substitutedphosphoric acid residue”, “optionally substituted carbocycle” or“optionally substituted heterocycle”, each may be substituted with thesame or different, 1 to 4 group(s) selected from Substituent group B atany position.

Examples of Substituent group B include hydroxy, carboxy, halogen (F,Cl, Br, I), halo lower alkyl (e.g., CF₃, CH₂CF₃, CH₂CCl₃), halo loweralkoxy (e.g., OCF₃, OCH₂CF₃, OCH₂CCl₃), lower alkyl (e.g., methyl,ethyl, isopropyl, tert-butyl), lower alkenyl (e.g., vinyl), loweralkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl(e.g., cyclopropenyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy,butoxy), lower alkenyloxy (e.g., vinyloxy, allyloxy), loweralkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl), nitro, nitroso, optionally substituted amino(e.g., alkylamino (e.g., methylamino, ethylamino, dimethylamino),acylamino (e.g., acetylamino, benzoylamino), aralkylamino (e.g.,benzylamino, trithylamino), hydroxyamino), azido, aryl (e.g., phenyl),aralkyl (e.g., benzyl), cyano, isocyano, isocyanate, thiocyanate,isothiocyanate, mercapt, alkylthio (e.g., methylthio), alkylsulfonyl(e.g., methansulfonyl, ethansulfonyl), optionally substitutedalkylsulfonylamino (e.g., methanesulfonylamino, ethansulfonylamino,N-methylsulfonyl-N′-methylamino), optionally substituted carbamoyl(e.g., alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl,dimethylcarbamoyl)), sulfamoyl, acyl (e.g., formyl, acetyl), formyloxy,haloformyl, oxal, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl,sulfino, sulfo, sulfoamino, hydrazino, azido, ureido, amizino,quanidino, phthalimide, oxo, phosphoric acid residue, lower alkyl whichis substituted with a phosphoric acid residue and may be intervened witha heteroatom group(s), aryl substituted with a phosphoric acid residue,aralkyl substituted with a phosphoric acid residue, hydroxyl loweralkyl, preferably hydroxy, carboxy, halogen (F, Cl, Br, I), halo loweralkyl (e.g., CF₃, CH₂CF₃, CH₂CCl₃), halo lower alkoxy (e.g., OCF₃,OCH₂CF₃, OCH₂CCl₃), lower alkyl (e.g., methyl, ethyl, isopropyl,tert-butyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy),optionally substituted amino (e.g., alkylamino (e.g., methylamino,ethylamino, dimethylamino), oxo, or phosphoric acid residue.

Examples of a substituent of “optionally substituted amino” or“optionally substituted carbamoyl” include mono- or di-lower alkyl,lower alkylcarbonyl, lower alkylsulfonyl, optionally substituted loweralkyl (e.g., methyl, ethyl, isopropyl, benzyl, carbamoylalkyl (e.g.,carbamoylmethyl), mono- or di-lower alkylcarbamoyl lower alkyl (e.g.,dimethylcarbamoylethyl), hydroxyl lower alkyl, heterocycle lower alkyl(e.g., morpholinoethyl, tetrahydropyranylethyl), alkoxycarbonyl loweralkyl (e.g., ethoxycarbonylmethyl, ethoxycarbonylethyl), mono- ordi-lower alkylamino lower alkyl (e.g., dimethylaminoethyl)), loweralkoxy lower alkyl (e.g., methoxyethyl, ethoxymethyl, ethoxyethyl,isopropoxyethyl), aoyl (e.g., formyl, optionally substituted loweralkylcarbonyl (e.g., acetyl, propionyl, butylyl, isobutylyl, valeryl,isovaleryl, pivaroyl, hexanoyl, octanoyl, methoxyethylcarbonyl,2,2,2-trifluoroethylcarbonyl, ethoxycarbonylmethylcarbonyl), loweralkoxy lower alkylcarbonyl (e.g., methoxyethylcarbonyl), loweralkylcarbamoyl lower alkylcarbonyl (e.g., methylcarbamoylethylcarbonyl),alkoxycarbonylacetyl), optionally substituted arylcarbonyl (e.g.,benzoyl, toloyl), optionally substituted aralkyl (e.g., benzyl,4-fluorobenzyl), hydroxy, optionally substituted lower alkylsulfonyl(e.g., methanesulfonyl, ethanesulfonyl, isopropylsulfonyl,2,2,2-trifluoroethanesulfonyl, benzylsulfonyl, methoxyethylaulfonyl),lower alkyl, or arylsulfonyl optionally substituted with halogen (e.g.,benzenesulfonyl, toluenesulfonyl, 4-fluorobenzenesulfonyl,fluorobonzenosulfonyl), cycloalkyl (e.g., cyclopropyl), aryl optionallysubstituted with lower alkyl (e.g., phenyl, trithyl), loweralkylaminosulfonyl (e.g., methylaminosulfonyl, dimethylaminosulfonyl),lower alkylaminocarbonyl (e.g., dimethylaminocarbonyl), loweralkoxycarbonyl (e.g., ethoxycarbonyl), cycloalkylcarbonyl (e.g.,cyclopropylcarbonyl, cyclohexylcarbonyl), optionally substitutedsulfamoyl (e.g., sulfamoyl, methylsulfamoyl, dimethylsulfamoyl), loweralkylcarbonylamino (e.g., methylcarbonylamino), heterocycle (e.g.,morpholino, tetrahydropyranyl), optionally substituted amino (e.g.,mono- or di-alkylamino (e.g., dimethylamino), formylamino).

As to amino of “optionally substituted amino”, “optionally substitutedcarbamoyl”, or “optionally substituted carbamoylcarbonyl”, twosubstituents on the amino together with the neighboring N atom may forman N-containing heterocycle which optionally contains S and/or O in thering (preferably 5- to 7-membered ring or saturated ring) and isoptionally substituted with oxo or hydroxy. The optional S atom in thering may be substituted with oxo. The N-containing heterocycle ispreferably a 5- or 6-membered ring such as piperadinyl, piperidino,morpholino, pyrrolidino, 2-oxopiperidino, 2-oxopyrrolidino,4-hydroxymorpholino.

“Phosphoric acid residue” means a group shown of the formula: —PO(OH)₂.“Optionally substituted phosphoric acid residue” means a phosphoric acidresidue wherein the OH part and/or a hydrogen of the OH is optionallysubstituted with a phosphoric acid residue, preferably shown by theformula:

-   (wherein, R^(A) and R^(B) each is independently OR^(C) or    NR^(D)R^(E) (wherein R^(C), R^(D) and R^(E) are each independently    hydrogen, optionally substituted lower alkyl, optionally substituted    cycloalkyl, optionally substituted aryl, optionally substituted    heterocyclic group, or R^(D) and R^(E) taken together with the    neighboring N atom may form an optionally substituted heterocycle    (preferably 5- to 6-membered ring)) or R^(A) and R^(B) taken    together with the neighboring P atom may form an optionally    substituted heterocycle (preferably 5- to 6-membered ring)).

Preferably, R^(A) and R^(B) are both OR^(C), or one of them is OR^(C)and the other is NR^(D)R^(E).

R^(C), R^(D) and R^(E) each is preferably, independently, lower alkyl(e.g., methyl, ethyl).

The optionally substituted heterocycle formed by R^(A) and R^(B) takentogether with the neighboring P atom may be the following structure:

(wherein, the broken line means a part of the ring)

Hydroxy substituted with optionally substituted phosphoric acid residueis preferably hydroxy substituted with a phosphoric acid residuesubstituted with di lower alkyls, and more preferably a group of theformula:

Amino substituted with optionally substituted phosphoric acid residue ispreferably amino substituted with a phosphoric acid residue substitutedwith di lower alkyls, and more preferably a group of the formula:

More Preferable Embodiments

R¹ is hydrogen or lower alkyl, preferably hydrogen.

X is a single bond, a heteroatom group selected from O, S, SO, SO₂ andNH (hereafter also referred to as “M”), or lower alkylene or loweralkenylene each may be intervened by the heteroatom. The term of“intervened by” means the following cases:

1) The heteroatom group is present between carbon atoms whichconstitutes the alkylene or alkenylene.2) The heteroatom group is attached to the N atom of the carbamoyl groupneighboring to X.3) The heteroatom group is attached to R² neighboring to X.

The heteroatom group (M) may be the same or different, and one or moreatoms.

Examples of that lower alkylene is intervened by a heteroatom groupinclude -M-CH₂—, —CH₂-M-CH₂—, —CH₂-M-, and —CH₂-M-M-CH₂—.

X is preferably a spacer consisting 1 to 3 joined atoms. X is morepreferably lower alkylene or lower alkenylene each may be intervened bya heteroatom group, or O. X is most preferably C1 to C3 alkylene, C2 toC3 alkenylene, or O. Especially preferred is methylene or O.

R² is optionally substituted aryl, preferably phenyl. A substituent onthe aryl is the same or different, 1 to 3, preferably 1 to 2substituent(s), including preferably halogen, hydroxy, amino, loweralkylamino, cyano, carboxy, formyl, oxo, lower alkyl, lower alkoxy,lower alkylthio, carbamoyl, and lower alkylcarbamoyl, and Substituentgroup S1 (: optionally substituted phosphoric acid residue, arylsubstituted with optionally substituted phosphoric acid residue, aralkylsubstituted with optionally substituted phosphoric acid residue,hydroxyl substituted with optionally substituted phosphoric acidresidue, amino substituted with optionally substituted phosphoric acidresidue, lower alkyl substituted with optionally substituted phosphoricacid residue (said lower alkyl may be intervened with a hetero atomgroup(s) selected from O, S, SO, SO₂, NR⁵ (R⁵ is independently selectedfrom the same substituent group for R⁴), —N═ and ═N—), lower alkoxylower alkyl, amino lower alkyl optionally substituted with mono- ordi-lower alkyl, halogenated lower alkyl, lower alkoxy, carbamoyloptionally substituted with mono- or di-lower alkyl, optionallysubstituted lower alkylsulfonylamino, halogenated lower alkoxy, hydroxyllower alkyl), more preferably halogen, hydroxy, amino, cyano, loweralkyl, lower alkoxy or Substituent group S1, and most preferred ishalogen (e.g., F) and/or a group selected from Substituent group S1. Asubstituent on the aryl is preferably at the 4-position. R² is morepreferably phenyl or phenyl substituted with at least halogen, and mostpreferably 4-halogenophenyl (e.g., 4-F-phenyl). In another embodiment,R² is preferably phenyl optionally substituted with 1 to 3 R(s)mentioned below.

In all compounds of the present invention, the structure of “X—R²” ispreferably shown by the formula below:

R each is independently a group selected from halogen and Substituentgroup S1.

Substituent group S1: optionally substituted phosphoric acid residue,aryl substituted with optionally substituted phosphoric acid residue,aralkyl substituted with optionally substituted phosphoric acid residue,hydroxyl substituted with optionally substituted phosphoric acidresidue, amino substituted with optionally substituted phosphoric acidresidue, lower alkyl substituted with optionally substituted phosphoricacid residue (said lower alkyl may be intervened by a heteroatomgroup(s) selected from CO, O, S, SO, SO₂, NR^(a) (R^(a) is hydrogen orlower alkyl), —N═ and ═N—), lower alkoxy lower alkyl, optionallysubstituted amino lower alkyl (the substituent: mono- or di-lower alkyl,lower alkylcarbonyl, or lower alkylsulfonyl), halogenated lower alkyl,lower alkoxy, optionally substituted carbamoyl (the substituent: mono-or di-lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl),optionally substituted lower alkylsulfonylamino, halogenated loweralkoxy, and hydroxyl lower alkyl.

m is an integer of 0 to 3, preferably 0 or 1 to 2. when m is 1, R ispreferably halogen. When m is 2, R is more preferably the same ordifferent group selected from halogen, lower alkyl, lower alkoxy, loweralkoxylower alkyl, halogenated lower alkyl, halogenated lower alkoxy,lower alkylsulfonylamino, carbamoyl, and lower alkylcarbamoyl. Morepreferably, R is two halogens, or halogen and another group. Rpreferably locates at the 4-position and optional another position ofthe benzene ring.

R³ can be a various substituent which does not bring a negative effectto the pharmacological activity, including hydrogen, halogen, hydroxy,optionally substituted lower alkyl, optionally substituted cycloalkyl,optionally substituted lower alkenyl, optionally substituted loweralkoxy, optionally substituted lower alkenyloxy, optionally substitutedaryl, optionally substituted aryloxy, optionally substitutedheterocyclic group, optionally substituted heterocycleoxy, andoptionally substituted amino. Examples of substituent of “optionallysubstituted” include halogen, hydroxy, amino, lower alkylamino, cyano,carboxy, formyl, oxo, lower alkyl, lower alkoxy, lower alkylthio,carbamoyl, lower alkylcarbamoyl, aryl, heterocyclic group, loweralkylcarbonyl, lower alkylcarbonyloxy, lower alkoxycarbonyl, halogenatedlower alkyl, halogenated lower alkoxy, and preferably halogen, hydroxy,amino, lower alkylamino, lower alkyl, and lower alkoxy. R³ is morepreferably hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, loweralkoxy, lower alkenyloxy or optionally substituted amino, and mostpreferably hydrogen or lower alkyl (e.g., methyl), esp. hydrogen.

Z² shows C, CH, optionally substituted lower alkylene, lower alkenyleneetc., and Z² and R⁴ of Z¹ taken together form a ring, whereby compound(I) shows a tricyclic compound (I-1) or (I-11) shown below, or itsderivative, tetracyclic compound.

A ring is optionally substituted heterocycle containing at least an Natom. The heterocycle is a 5- to 7-membered ring which containspreferably 1 to 3, more preferably 2 to 3 atoms of O, S and/or N. Theheterocycle is preferably selected from the above heterocycle. The arcoptionally contains 1 to 2 heteroatom(s) at any possible position. Oneof preferable embodiments of A ring is an optionally substituted ringshown below.

(Z is CH₂, O, S, SO, SO₂ or NR¹⁹)

A ring is preferably a ring of (a), (b), or (c).

Z is preferably O or NR¹⁹.

When Z is NR¹⁹, examples of R¹⁹ include 1) hydrogen, 2) optionallysubstituted lower alkyl (the substituent is e.g., amino optionallysubstituted with mono- or di-lower alkyl; cycloalkyl; hydroxy;optionally substituted heterocyclic group (preferably 5- to 7-memberedring, e.g., furyl, thienyl, thiazolyl, pyridil, morpholino, imidazole;examples of the substituent include lower alkyl, halogen); optionallysubstituted heterocyclecarbonyl (the heterocycle is preferably 5- to7-membered ring, e.g., morpholinocarbonyl); optionally substitutedphenyl (the substituent is e.g., lower alkyl, amino, lower alkylamino,hydroxy, halogen, halogenated lower alkyl, lower alkoxy, halogenatedlower alkoxy, lower alkylthio, lower alkylsulfonyl), acetylamino,carbamoyl, carbamoyl substituted with mono- or di-lower alkyl, loweralkylsulfonylamino, lower alkoxy, carbonyl, halogen, thiol, loweralkylthio), 3) lower alkenyl, 4) acyl (e.g., lower alkylcarbonyl), 5)lower alkylsulfonyl. R¹⁹ may be selected from Substituent group S2 shownbelow.

The other substituent on A ring may be selected from R¹⁵ to R¹⁸ orSubstituent group S2, preferably lower alkyl. Substituents on A ring mayform a condensed ring or a spiro ring as mentioned below, wherebycompound (I) includes a tetracyclic compound.

A ring is more preferably any of the following rings:

-   (wherein, R²⁰ to R⁴⁰ are each independently a group selected from    Substituent group S2, or any two groups of R²⁰ to R⁴⁰, which bonds    to the same carbon atom, taken together with the carbon atom, may    form a spiro ring, i.e., an optionally substituted carbocycle or    optionally substituted heterocycle, or each combination of (R²⁰ and    R²²), (R²³ and R²⁴), (R²⁵ and R²⁶), (R²⁷ and R²⁹), (R³⁰ and R³¹),    (R³² and R³⁴), (R³⁵ and R³⁶), (R³⁷ and R³⁸), and (R³⁹ and R⁴⁰),    taken together with the neighboring atom, may form an optionally    substituted carbocycle or optionally substituted heterocycle.

Substitution group S2: hydrogen, optionally substituted lower alkyl,optionally substituted cycloalkyl, optionally substituted cycloalkyllower alkyl, optionally substituted lower alkenyl, optionallysubstituted lower alkoxy, optionally substituted lower alkenyloxy,optionally substituted aryl, optionally substituted aryl lower alkyl,optionally substituted aryloxy, optionally substituted heterocycle,optionally substituted heterocycle lower alkyl, optionally substitutedheterocycleoxy, hydroxy, optionally substituted amino, optionallysubstituted lower alkylcarbonyl, optionally substitutedcycloalkylcarbonyl, optionally substituted cycloalkyl loweralkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionallysubstituted arylcarbonyl, optionally substituted aryl loweralkylcarbonyl, optionally substituted aryl oxycarbonyl, optionallysubstituted heterocyclecarbonyl, optionally substituted heterocyclelower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl,optionally substituted aminocarbonyl, optionally substituted phosphoricacid residue, aryl substituted with optionally substituted phosphoricacid residue, aralkyl substituted with optionally substituted phosphoricacid residue, hydroxy substituted with optionally substituted phosphoricacid residue, amino substituted with optionally substituted phosphoricacid residue, or lower alkyl substituted with optionally substitutedphosphoric acid residue (the lower alkyl may be intervened with aheteroatom group(s) selected from CO, O, S, SO, SO₂, NR⁵ (R⁵ isindependently selected from the same substitution group as R⁴), —N═ and═N—)

The stereochemistry of an asymmetric carbon represented by * shows theR- or S-configuration, or a mixture thereof)

In one embodiment, R²⁰ to R⁴⁰ each is preferably hydrogen, optionallysubstituted lower alkyl (examples of the substituent: OH, lower alkoxy,cycloalkyl, lower alkylthio, lower alkylsulfonyl, heterocyclic group,aryl, optionally substituted amino (examples of the substituent: loweralkyl, acyl)), cycloalkyl, optionally substituted aryl (examples of thesubstituent: OH, lower alkyl), and optionally substituted heterocyclicgroup.

In one embodiment, R²⁰ to R²⁵, R²⁷ to R³⁰, and R³² to R³⁹, each ispreferably hydrogen, C1-C8 alkyl, C6-C14 aryl C1-C8 alkyl, C6-C14 aryl,or alkoxy.

In one embodiment, R²⁶, R³¹, and R⁴⁰, each is preferably hydrogen, C3-6cycloalkyl, heterocycle, or C1-8 alkyl optionally substituted withhydroxy, C3-6 cycloalkyl, alkoxy, heterocycle, heteroaryl, C6-14 aryl,or amino, wherein said amino may be optionally substituted with—C(O)C1-8 alkyl or C1-8 alkyl.

More Preferred embodiments are shown below for example

I) When A ring is A-1, preferred is that 1) Z is NR²⁶ and R²⁶ and R²⁴taken together form heterocycle, and the others are hydrogens; 2) Z is Oor NR²⁶, (R²⁰ and R²²) or (R²³ and R²⁴) taken together form cycloalkylwhich is substituted with phenyl, the others are hydrogens or optionallysubstituted lower alkyl.

II) When A ring is A-2, preferred is that 1) Z is O, R²⁷ or R²⁸ is loweralkyl, and the others are hydrogens; 2) Z is NR³¹ and R³⁰ and R³¹ takentogether form heterocycle and the others are hydrogens, or R²⁷ and R²⁹taken together form cycloalkyl and the others are hydrogens; 3) Z is O,R²⁷ and R²⁹ taken together form cycloalkyl which may be condensed withphenyl, and the others are hydrogens

R¹⁴ and R^(x) are each independently hydrogen, optionally substitutedlower alkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkyl lower alkyl, optionally substituted lower alkenyl, optionallysubstituted lower alkoxy, optionally substituted lower alkenyloxy,optionally substituted aryl, optionally substituted aryl lower alkyl,optionally substituted aryloxy, optionally substituted heterocyclicgroup, optionally substituted heterocycle lower alkyl, optionallysubstituted heterocycleoxy, hydroxy, optionally substituted amino,optionally substituted lower alkylcarbonyl, optionally substitutedcycloalkylcarbonyl, optionally substituted cycloalkyl loweralkylcarbonyl, optionally substituted lower alkoxycarbonyl, optionallysubstituted arylcarbonyl, optionally substituted aryl loweralkylcarbonyl, optionally substituted aryloxycarbonyl, optionallysubstituted heterocyclecarbonyl, optionally substituted heterocyclelower alkylcarbonyl, optionally substituted heterocycleoxycarbonyl,optionally substituted amninocarbonyl, optionally substituted phosphoricacid residue, aryl substituted with optionally substituted phosphoricacid residue, aralkyl substituted with optionally substituted phosphoricacid residue, hydroxy optionally substituted with optionally substitutedphosphoric acid residue, amino substituted with optionally substitutedphosphoric acid residue, or lower alkyl substituted with optionallysubstituted phosphoric acid residue (the lower alkyl may be intervenedwith a heteroatom group(s) selected from O, S, SO, SO₂, NR^(a) (R^(a) ishydrogen or lower alkyl), —N═ and ═N—).

R¹⁴ and R^(x) are each independently, preferably, hydrogen, hydroxyl,optionally. substituted lower alkyl (the substituent is preferably,e.g., amino, lower alkyl amino, hydroxy, lower alkoxy). R¹⁴ and R^(x)are preferably hydrogens.

A broken line in the compound (I-1) represents the presence or absenceof a bond, provided that when the broken line represents the presence ofa bond, R^(X) is not present.

The compound (I) includes the following compounds.

(wherein each symbol is as defined above)

F ring means the same heterocycle as A ring, preferably 5- to 7-memberedring, and the substituents on F ring are the same as those for A ring.The other symbols are as defined above.

(wherein each symbol is as defined above; Z is O or NR¹⁹; R¹⁵ to R¹⁹ areeach independently hydrogen or a group selected from the aboveSubstituent group S2, or each combination of (R¹⁵ and R¹⁶), (R¹⁷ andR¹⁸), (R¹⁶ and R¹⁸), and (R¹⁸ and R¹⁹) taken together with theneighboring atom(s), may form an optionally substituted carbocycle(preferably 5- to 6-membered ring) or an optionally substitutedheterocyle (preferably 5- to 6-membered ring); or each combination of(R¹⁵ and R¹⁶) and (R¹⁷ and R¹⁸) taken together may form oxo)

Compound (I-3) is preferably as follows.

(1) R¹ is hydrogen; Rs is hydrogen; m is 1 or 2; R¹⁴ is hydrogen.(2) m is 1 or 2, R is each independently halogen, halogenated loweralkyl, lower alkoxy, halogenated lower alkoxy, lower alkoxy lower alkyl,hydroxy lower alkyl, optionally substituted amino lower alkyl (thesubstituent is mono- or di-lower alkyl, lower alkylcarbonyl, or loweralkylsulfonyl), optionally substituted carbamoyl (the substituent ismono- or di-lower alkyl, lower alkylcarbonyl, or lower alkylsulfonyl),phosphoric acid residue, aryl substituted with optionally substitutedphosphoric acid residue, aralkyl substituted with optionally substitutedphosphoric acid residue or sulfonylamino optionally substituted withlower alkyl; R¹ is hydrogen; R³ is hydrogen; R¹⁴ is hydrogen, hydroxylor lower alkyl optionally substituted with mono- or di-lower alkylamino;Z is O or NR¹⁹ (R¹⁹ is hydrogen or lower alkyl, lower alkoxy loweralkyl, optionally substituted phosphoric acid residue, aryl substitutedwith optionally substituted phosphoric acid residue, aralkyl substitutedwith optionally substituted phosphoric acid residue, hydroxy substitutedwith optionally substituted phosphoric acid residue, amino substitutedwith optionally substituted phosphoric acid residue, or lower alkylsubstituted with optionally substituted phosphoric acid residue). (3)Ris each independently, —F, —CF₃, —OMe, —OCF₃, —CH₂OMe, —CH₂OH,—CH₂N(Me)₂, —CONHMe, —CON(Me)₂, —CH₂PO(OEt)₂, —PO(OEt)₂, —NHSO₂Me, or—NMeSO₂Me; R¹ is hydrogen; R is hydrogen; m is 1 or 2; R¹⁴ is hydrogen,hydroxyl or —CH₂N(Me)₂; Z is O or NR¹⁹ (R¹⁹ is hydrogen or —CH(Me)₂,—(CH₂)₂OMe, —(CH₂)₂PO(OEt)₂).(4) R¹⁵ and R¹⁶ are hydrogens; R¹⁷ and R¹⁸ are hydrogens or takentogether with the neighboring atom form q 3- to 7-membered carbocycle;and/or Z is O or NH. This case preferably also satisfies the above (2)or (3).

D ring means the same heterocycle as A ring, preferably 5- to 7-memberedring, and the substituents on D ring are the same as those for A ring.The other symbols are as defined above.

The structure of compound (I) has at least the followingcharacteristics.

(1) The main structure, condensed heterocycle, is substituted with oxo(═O), hydroxyl (OH) and oxo.(2) A substituted carbamoyl group (—CONR¹XR²) is attached to theposition neighboring to the oxo group on the condensed heterocycle.

The above structure contributes to a remarkably potent integraseinhibitory activity and/or cell-growth inhibitory activity against virusincluding HIV. In contrast, the structures of the other parts such asZ¹, Z², and R³ each may be of variety, being optionally substituted oroptionally condensed, and its condensed ring is also optionallysubstituted.

The present invention provides a pharmaceutically acceptable salt or asolvate of compound (I). All theoretically possible tautomer,geometrical isomer, optically active compound, and racemate thereof arewithin the scope of the invention.

Pharmaceutically acceptable salts of a compound of the present inventioninclude, as basic salts, for example, alkali metal salts such as sodiumor potassium salts; alkaline-earth metal salts such as calcium ormagnesium salts; ammonium salts; aliphatic amine salts such astrimethylamine, triethylamine, dicyclohexylamine, ethanolamine,diethanolamine, triethanolamine or procaine salts; aralkyl amine saltssuch as N, N-dibenzylethylenediamine salts; heterocyclic aromatic aminesalts such as pyridin salts, picoline salts, quinoline salts orisoquinoline salts; quaternary ammonium salts such astetramethylammonium salts, tetraethylammonium salts,benzyltrimethylammonium salts, benzyltriethylammonium salts,benzyltributylammonium salts, methyltrioctylammonium salts ortetrabutylammonium salts; and basic amino acid salts such as argininesalts or lysine salts. Acid salts include, for example, mineral acidsalts such as hydrochloride, sulfates salts, nitrate salts, phosphatessalts, carbonates salts, hydrogencarbonates or perchlorate; organic acidsalts such as acetates, propioinates, lactates, maleates, fumarates,tararic acid salts, malates, citrates salts, ascorbates, formic acid;sulfonates such as methanesulfonates, isethionates, benzenesulfonates,or p-toluenesulfonates; and acidic amino acid salts such as aspartatesor glutamates.

Solvates of a compound of the present invention include alcholates andhydrates.

A general process for producing the present compound will be exemplifiedbelow.

(Method of Preparing Raw Material)

(wherein L¹ is a leaving group (e.g.; halogen); P¹ and P² are a hydroxyprotecting group; P³ is a carboxy protecting group (e.g.: lower alkyl);R^(a) and R^(b) are hydrogen or a substituent on an amino group)

Examples of a hydroxy protecting group (P¹, P²) include acyl (e.g.:acetyl, pivaloyl, benzoyl), aralkyl (e.g.: benzyl), lower alkyl (e.g.:methyl), alkoxyalkyl (e.g.: methoxymethyl, methoxyethyl), loweralkylsulfonyl (e.g.: methanesulfonyl), arylsulfonyl (e.g.:benzenesulfonyl, toluenesulfonyl), alkoxycarbonyl (e.g.:methoxycarbonyl) and the like.

As a carboxy protecting group (P³), lower alkyl (e.g.; methyl, ethyl),and aralkyl (e.g.: benzyl) are exemplified.

(First Step)

The present step is a reaction for condensing a compound (II) and acompound (III) to synthesize a compound (IV). The reaction may beperformed according to the condition for a reaction of amidatingcarboxylic acid which is generally performed. A compound (II) may bereacted as it is, or may be reacted after converted into correspondingacid chloride or active ester. Preferably, the reaction is performed ina suitable solvent in the presence of a condensing agent.

As a condensing agent, dicyclohexylcarbodiimide,1-ethyl-S-(3-dimethylaminopropyl)carbodiimide hydrochloride and the likemay be used. If necessary, a reagent such as 1-hydroxybenzotriazole andN-hydroxysuccinimide, or a base such as triethylamine,N-methylmorpholine, and pyridine may be added.

A reaction temperature is 0 to 150° C., preferably room temperature to70° C.

As a reaction solvent, a non-protonic solvent can be broadly used, andtetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylenechloride, chloroform and the like are preferable.

A reaction time is a few minutes to a few tens hours, preferably 9 to 17hours.

(Second Step)

The present step is a reaction for introducing a protected hydroxy group(OP¹) into a compound (IV) to produce a compound (V), The reaction maybe performed according to the condition for an alkoxylating reactionwhich is generally performed.

For example, a compound (V) in which P¹ is methyl can be synthesized byreacting a compound (IV) with metal alkoxide (e.g.: sodium methoxide).

A reaction temperature is 0 to 200° C. preferably 80 to 120° C.

As a reaction solvent, alcohol, dimethylformamide (DM), and dimethylsulfoxide (DMSO) are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 5 to 10hours.

(Third step)

The present step is a reaction for protecting a hydroxy group of acompound (V) to produce a compound (VI). The reaction may be performedaccording to the condition for a reaction of protecting a hydroxy groupwhich is generally performed. For example, by using diisopropylazodicarboxylate or diethyl azodicarboxylate together with an alcoholand various phosphines, a compound (VI) in which P² is alkyl can besynthesized.

A reaction temperature is 0 to 100° C., preferably 0° C. to roomtemperature.

As a reaction solvent, THF, toluene, dichloromethane and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 3hours.

(Fourth Step)

The present step is a reaction of oxidizing a nitrogen atom of acompound (VI) to produce a compound (VII). The reaction may be performedaccording to the condition for an oxidation reaction using an oxidizingagent which is generally performed.

A reaction temperature is 0 to 100° C., preferably under ice-cooling toroom temperature.

As a reaction solvent, chloroform, methylene chloride, acetic acid andthe like are exemplified.

Examples of an oxidizing agent include metachloroperbenzoic acid,hydrogen peroxide and the like.

A reaction time is a few minutes to a few tens hours, preferably 1 to 5hours.

(Fifth Step)

The present step is a reaction for hydroxylating a methyl group of acompound (VII). Preferably, after acetoxylation by a reaction withacetic anhydride (reaction temperature: 0 to 150° C., preferably 120 to140° C.), this may be hydrolyzed (e.g.: treatment with a base (e.g.:alkali metal hydroxide)).

A reaction time is a few minutes to a few tens hours, preferably 0.5 to2 hours for acetoxylation, and 0.5 to 1 hour for hydrolysis.

(Sixth Step)

The present step is a reaction for oxidizing a hydroxy group of acompound (VIII) to synthesize a compound (IX).

A reaction temperature is 0 to 150° C., preferably room temperature to70° C.

As a reaction solvent, chloroform and the like are exemplified.

As an oxidizing agent, dimethyl sulfoxide and the like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 0.1 to1 hour.

(Seventh Step)

The present step is a reaction for oxidizing a formyl group of acompound OX) to synthesize a compound (X).

A reaction temperature is 0 to 150° C., preferably under ice-cooling toroom temperature.

As a reaction solvent, an alcohol and the like are exemplified.

As an oxidizing agent, potassium hydroxide and iodine are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 0.5 to3 hours.

(Eighth Step)

The present step is a reaction for deprotecting an OP² part of acompound (X) to synthesize a compound (XI). The reaction may beperformed according to the condition for a reaction of deprotecting ahydroxy protecting group which is generally performed.

A reaction temperature is 0 to 150° C., preferably under ice-cooling toroom temperature.

As a reaction solvent, acetonitrile, methylene chloride, THF and thelike are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 3hours.

(Ninth Step)

The present step is a reaction for deprotecting an OP¹ part of acompound (XI) to synthesize a compound (I-A). The reaction may betreated preferably with a Lewis acid (e.g.: aluminum chloride).

A reaction temperature is 0 to 150° C., preferably 10 to 60° C.

As a reaction solvent, methylene chloride, THF and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 3hours.

(Tenth Step)

The present step is a reaction for deprotecting an ester part (COOP³) ofa compound (X) to synthesize carboxylic acid (XII). Preferably,hydrolysis with an alkali (e.g.: NaOH) may be performed.

A reaction temperature is 0 to 150° C., preferably 10 to 50° C.

As a reaction solvent, methanol, water and the like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably a fewminutes to 2 hours.

Carboxylic acid (XII) can be converted into various derivatives (e.g.;amide).

(Eleventh Step)

The present step is a reaction for reacting a compound (XII) withvarious amines to synthesize a compound (XIII). The reaction may beperformed according to the condition for a reaction of amidatingcarboxylic acid which is generally performed and, for example, thereaction may be performed as in the first step.

A reaction temperature is 0 to 150° C., preferably room temperature to70° C.

As a reaction solvent, a non-protonic solvent can be broadly used, andtetrahydrofuran (THF), 1,4-dioxane, dimethylformamide (DMF), methylenechloride, chloroform and the like are preferable.

A reaction time is a few minutes to a few tens hours, preferably a fewminutes to 3 hours.

An amide part of the resulting compound (XIII) may be further chemicallymodified (e.g.: N-alkylation).

(Twelfth Step)

The present step is a reaction for deprotecting OP¹ and OP² parts of acompound (XIII) to synthesize a compound (I-B). The reaction may beperformed according to the condition for a reaction of deprotecting ahydroxy protecting group which is generally performed.

For example, when pyridine hydrochloride is used, a reaction temperatureis 0 to 200° C., preferably 150 to 180 degree.

A reaction time is a few minutes to a few tens hours, preferably 1 to 5minutes.

(Thirteenth Step)

The present step is a reaction for deprotecting an ester part (COOP³) ofa compound (XI) to synthesize carboxylic acid (XIV). Preferably,hydrolysis with an alkali (e.g.: lithium hydroxide) may be performed.

A reaction temperature is 0 to 150′C, preferably 10 to 50° C.

As a reaction solvent, methanol, water and the like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably a fewminutes to 3 hours.

(Fourteenth Step)

The present step is a reaction for deprotecting an OPS part of acompound (XIV) to synthesize a compound (I-C). The reaction may betreated preferably with a Lewis acid (e.g.: boron tribromide).

A reaction temperature is 0 to 150° C., preferably under ice-cooling toroom temperature.

As a reaction solvent, dichloromethane and the like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably a fewminutes to 5 hours.

The monocyclic carbamoylpyridone derivative obtained above is derivedinto a bicyclic compound by the following method.

(Process 1)

(wherein R¹, X, R², P¹, P³ and R⁴ are as define above, and L² is aleaving group such as halogen etc.)

(Fifteenth Step)

The present step is a reaction for reacting the compound (XI) or acompound (XI′) which is a tautomer thereof with an allyl compound tosynthesize a compound (XV). A compound (XI′) can be synthesized, forexample, according to the method of Example A-1.

The reaction is performed preferably in the presence of a base (e.g.:cesium carbonate).

A reaction temperature is 0 to 100° C., preferably 10 to 40° C.

As a reaction solvent, dimethylformamide and the like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 10hours.

(Sixteenth Step)

The present step is a reaction for oxidizing a compound (XV) tosynthesize a compound (XVI). As an oxidizing agent, osmium tetraoxideand alkali metal osmium tetraoxide (e.g.: K₂OsO₄) are exemplified.

A reaction temperature is 0 to 100° C., preferably 10 to 40′C.

As a reaction solvent, 1,4-dioxane, tetrahydrofuran and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 5hours.

(Seventeenth Step)

The present step is a reaction for reacting a compound (XVI) with amine(XVII) to perform dehydration condensation to synthesize a compound(XVIII).

A reaction temperature is 0 to 200° C., preferably 140 to 180° C.

As a reaction solvent, methylene chloride, acetonitrile and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 0.5 to1.5 hours.

(Eighteenth Step)

The present step is a reaction for deprotecting a compound (XVIII)preferably with an acid to synthesize a compound (XIX), and may beperformed according to the condition for a conventional reaction ofdeprotecting a protected hydroxy group.

A reaction temperature is 0 to 200° C.

As an acid, pyridine hydrochloride, trifluoroacetic acid and the likeare exemplified.

As a reaction solvent, the acid and trimethylsilyl iodide areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 15minutes to 1 hour.

(Nineteenth Step)

The present step is a reaction for reducing a compound (XVIII) tosynthesize a compound (XX).

As a reducing agent, H₂/Pd.C and the like are exemplified.

A reaction temperature is 0 to 100° C., preferably 10 to 30° C.

As a reaction solvent, dimethylformamide, methanol, tetrahydrofuran andthe like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 5 to 20hours.

(Process 2)

The intermediate (XVIII) may be also synthesized by a method shownbelow.

(Twentieth Step)

The present step is a reaction for reacting a compound (XIV) with acompound (XXI) to synthesize a compound (XXII). The present reaction maybe performed according to the condition for a conventional amidationreaction.

A reaction temperature is 0 to 100° C., preferably 0 to 50° C.

As a reaction solvent, dimethylformamide, methylene chloride,tetrahydrofuran and the like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 10hours.

(Twenty-First Step)

The present step is a reaction for reacting a compound (XXII) with anacid to perform deprotection and intramolecular ring closure, tosynthesize a compound (XXIII). The present reaction may be performedaccording to the condition for a conventional reaction of deprotectingacetal.

A reaction temperature is 0 to 100° C., preferably room temperature to80° C.

As a reaction solvent, dioxane, tetrahydrofuran and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 0.5 to1 hour.

As an acid, hydrochloric acid, and paratoluenesulfonic acid areexemplified.

(Twenty-Second Step)

The present step is a reaction for dehydrating a compound (XXIII) tosynthesize a compound (XXIV). The present reaction may be performedaccording to the condition for a conventional dehydration reaction.

A reaction temperature is 0 to 100° C., preferably room temperature to80° C.

As a reaction solvent, acetonitrile, methylene chloride and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 6hours.

(Process 3)

(Twenty-Third Step)

The present step is a reaction for reacting a compound (XVI) with amine(XXIV) to perform dehydration condensation to synthesize a compound(XXV) according to the seventeenth step or a method of synthesizing acompound 17-1. Preferably, as a reaction catalyst, an acid (e.g.: aceticacid) is added, and a microwave reaction apparatus is used.

A reaction temperature is 0 to 200° C., preferably 140 to 180° C.

As a reaction solvent, methylene chloride, acetonitrile and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 0.5 to1.5 hours.

(Twenty-Fourth Step)

The present step is a reaction for deprotecting a compound (XXV)preferably with an acid to synthesize a compound (XXVI) according to theeighteenth step, and may be performed according to the condition for aconventional reaction of deprotecting a protected hydroxy group.

A reaction temperature is 0 to 200° C.

As an acid, pyridine hydrochloride, trifluoroacetic acid and the likeare exemplified.

As a reaction solvent, the aforementioned acid and trimethylsilyl iodideare exemplified.

A reaction time is a few minutes to a few tens hours, preferably 15minutes to 1 hour.

(Process 4)

(Twenty-Fifth Step)

The present step is a reaction for reacting a compound (XIV) with acompound (XXIV) to synthesize a compound (XXVII) according to thetwentieth step. The present reaction may be performed according to thecondition for a conventional amidation reaction.

A reaction temperature is 0 to 100° C., preferably 0 to 50° C.

As a reaction solvent, dimethylformamide, methylene chloride,tetrahydrofuran and the like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 10hours.

(Twenty-Sixth Step)

The present step is a reaction for reacting a compound (XXVII) or atautomer thereof with an allyl compound to synthesize a compound(XXVIII) according to the fifteenth step.

A reaction is performed preferably in the presence of a base (e.g.:cesium carbonate).

A reaction temperature is 0 to 100′C, preferably 10 to 40° C.

As a reaction solvent, dimethylformamide and the like are exemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 10hours.

(Twenty-Seventh Step)

The present step is a reaction for oxidizing a compound (XXVIII) tosynthesize a compound (XXIX) according to the sixteenth step.

As an oxidizing agent, osmium tetraoxide and alkali metal osmiumtetraoxide (e.g.: K₂OsO₄) are exemplified.

A reaction temperature is 0 to 100° C., preferably 10 to 40° C.

As a reaction solvent 1,4-dioxane, tetrahydrofuran and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 1 to 5hours.

(Twenty-Eighth Step)

The present step is a reaction for dehydration-condensing a compound(XXIX) to synthesize a compound (XXX) according to the seventeenth stepor a method of synthesizing a compound 17-1. Preferably, as a reactioncatalyst, an acid (e.g.: acetic acid) is added, and a microwave reactionapparatus is used.

A reaction temperature is 0 to 200° C., preferably 140 to 180° C.

As a reaction solvent, methylene chloride, acetonitrile and the like areexemplified.

A reaction time is a few minutes to a few tens hours, preferably 0.5 to1.5 hours.

(Twenty-Ninth Step)

The present step is a reaction for deprotecting a compound (XXX)preferably with an acid to synthesize a compound (XXXI) according to theeighteenth step, and may be performed according to the condition for aconventional reaction of deprotecting a protected hydroxy group.

A reaction temperature is 0 to 200° C.

As an acid, pyridine hydrochloride, trifluoroacetic acid and the likeare exemplified.

As a reaction solvent, the aforementioned acid and trimethylsilyl iodideare exemplified.

A reaction time is a few minutes to a few tens hours, preferably 15minutes to 1 hour.

(Process 5)

A compound (I-3) in which Z is NR¹⁹ can be synthesized according to thefollowing reaction scheme, according to Process 4.

(Process 10)

(wherein respective symbols are as defined above)

(Forty-Ninth Step)

A compound (XIV-16) is obtained by reacting a compound (XIV) with anamine reagent, according to the thirty-fifth step.

(Fiftieth Step)

A compound (XIV-17) is obtained by subjecting a compound (XIV-16) to ageneral acetal deprotecting reaction according to the forty-fourth step.

(Fifty-First Step)

A compound (XIV-18) is obtained (D ring formation) by deprotecting a P¹part of a compound (XIV-14) according to the thirty-eighth step.

The present invention further provides various intermediates (I-P) shownbelow and a process for preparing the same, as well as a process forpreparing the above mentioned compound (I) comprising the deprotectionof the intermediate.

Intermediates

(P¹ is a hydroxyl-protecting group; the other symbols are as definedabove)

Preferred compounds are shown below. Each P¹ is a hydroxyl-protectinggroup, such as C₆₋₁₄arylC₁₋₈alkyl (e.g., benzyl (═Bn)).

Preferably, wherein R^(e) is one or two halogen; R^(z) is C₁₋₈alkyl,C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryl, or alkoxy; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; R^(z) is C₁₋₈alkyl,C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryl, or alkoxy; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; R^(z) is C₁₋₈alkyl;R^(z1) is hydrogen, C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyl optionallysubstituted with hydroxy, C₃₋₆cycloalkyl, alkoxy, heterocycle,heteroaryl, C₆₋₁₄aryl, or amino, wherein said amino may be optionallysubstituted with —C(O)C₁₋₈alkyl or C₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; R^(z) is C₁₋₈alkyl;R^(z1) is hydrogen, C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyl optionallysubstituted with hydroxy, C₃₋₆cycloalkyl, alkoxy, heterocycle,heteroaryl, C₆₋₁₄aryl, or amino, wherein said amino may be optionallysubstituted with —C(O)C₁₋₈alkyl or C₁₋₈alkyl; and P¹ isC₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; R^(z1) is hydrogen,C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyl optionally substituted withhydroxy, C₃₋₆cycloalkyl, alkoxy, heterocycle, heteroaryl, C₆₋₁₄aryl, oramino, wherein said amino may be optionally substituted with—C(O)C₁₋₈alkyl or C₁₋₈alkyl; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is one or two halogen; R^(z1) is hydrogen,C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyl optionally substituted withhydroxy, C₃₋₆cycloalkyl, alkoxy, heterocycle, heteroaryl, C₆₋₁₄aryl, oramino, wherein said amino may be optionally substituted with—C(O)C₁₋₈alkyl or C₁₋₈alkyl; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;

Preferably, wherein R^(e) is halogen; and P¹ is C₆₋₁₄arylC₁₋₈alkyl;

The above intermediates, compound (I-20a), (I-20b), (I-21a), (I-21b),(I-22a), (I-22b), (I-23a), (I-23b), (I-24a), (I-24b), (I-25), (I-26), or(I-27), can be prepared by condensing a compound of the formula:

-   -   wherein R^(e) is one or two halogen; and R⁵⁰ is C₁₋₈alkyl;        with each amine shown below, respectively:

wherein R^(e) is C₁₋₈alkyl, C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryl, or alkoxy;

wherein R^(z) is C₁₋₈alkyl, C₆₋₁₄arylC₁₋₈alkyl, C₆₋₁₄aryl, or alkoxy;

wherein R^(z) is C₁₋₈alkyl; R^(z1) is hydrogen, C₃₋₆cycloalkyl,heterocycle, or C₁₋₈alkyl optionally substituted with hydroxy,C₃₋₆cycloalkyl, alkoxy, heterocycle, heteroaryl, C₆₋₁₄aryl, or amino,wherein said amino may be optionally substituted with —C(O)C₁₋₈alkyl orC₁₋₈alkyl;

wherein R^(z) is C₁₋₈alkyl; R^(z1) is hydrogen, C₃₋₆cycloalkyl,heterocycle, or C₁₋₈alkyl optionally substituted with hydroxy,C₃₋₆cycloalkyl, alkoxy, heterocyle, heteroaryl, C₆₋₁₄aryl, or amino,wherein said amino may be optionally substituted with —C(O)C₁₋₈alkyl orC₁₋₈alkyl;

wherein R^(z) is hydrogen, C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyloptionally substituted with hydroxy, C₃₋₆cycloalkyl, alkoxy,heterocycle, heteroaryl, C₆₋₁₄aryl, or amino, wherein said amino may beoptionally substituted with —C(O)C₁₋₈alkyl or C₁₋₈alkyl;

wherein R^(z1) is hydrogen, C₃₋₆cycloalkyl, heterocycle, or C₁₋₈alkyloptionally substituted with hydroxy, C₃₋₆cycloalkyl, alkoxy,heterocycle, heteroaryl, C₆₋₁₄aryl, or amino, wherein said amino may beoptionally substituted with —C(O)C₁₋₈alkyl or C₁₋₈alkyl;

The condition for the above condensation is illustrated below forexample.

Examples of the solvent include halocarbons such as dichloromethane,dichloroethane, and acetic acid.

The reaction temperature is preferably, 0 to 200° C., more preferably,50 to 170° C.

The reaction time is usually several minutes to several hours.

The above intermediates, compound (I-20a), (I-20b), (I-21a), (I-21b),(I-22a), (I-22b), (I-23a), (I-23b), (I-24a), (I-24b), (I-25), (I-26), or(I-27), can be deprotected to give each corresponding deprotectedcompound wherein P¹ is hydrogen, or its pharmaceutically acceptablesalt, which are encompassed within the scope of compound (I) of thepresent invention.

In addition, the present compound obtained above may be furtherchemically modified to synthesize another compound. In addition, whenthere is a reactive functional group (e.g.: OH, COOH, NH₂) on a sidechain part etc. in the above reaction, the group may be protected beforethe reaction and may be deprotected after the reaction, if desired.

The present compound is useful, for example, as a drug such as ananti-virus drug. The present compound has the remarkable inhibitoryaction on integrase of a virus. Therefore, the present compound can beexpected to have the preventive or therapeutic effect for variousdiseases derived from a virus which produces at least integrase, and isgrown at infection in an animal cell, and is useful as an integraseinhibiting agent for retrovirus (e.g. HIV-1, HIV-2, HTLV-1, SIV, FIVetc.), and is useful as an anti-HIV drug etc.

In addition, the present compound may be used in joint use therapy bycombining an anti-HIV drug having the different action mechanism such asa reverse trascriptase inhibitor and/or a protease inhibiting agent.Particularly, currently, an integrase inhibitor is not marketed, and itis useful to use in joint use therapy by combining the present compoundwith a reverse transcriptase inhibitor and/or a protease inhibitor.

Further, the above use includes not only use as a medical mixture foranti-HIV, but also use as a joint use agent for increasing the anti-HIVactivity of other anti-HIV drug such as cocktail therapy.

In addition, the present compound can be used in order to preventinfection with a retrovirus vector from spreading into a tissue otherthan an objective tissue, upon use of a retrovirus vector based on HIVor MLV in the field of gene therapy. Particularly, when a cell isinfected with a vector in vitro, and the cell is returned into a body,if the present compound is administered in advance, extra infection canbe prevented in a body.

The present compound can be administered orally or parenterally. In thecase of oral administration, the present compound can be also used as aconventional preparation, for example, as any dosage form of a solidagent such as tablets, powders, granules, capsules and the like; anaqueous agent; an oily suspension; or a liquid agent such as syrup andelixir. In the case of parenteral administration, the present compoundcan be used as an aqueous or oily suspension injectable, or a nasaldrop. Upon preparation of it, conventional excipients, binders,lubricants, aqueous solvents, oily solvents, emulsifiers, suspendingagents, preservatives, stabilizers and the like may be arbitrarily used.As an anti-HIV-drug, particularly, an oral agent is preferable. Apreparation of the present invention is prepared by combining (e.g.mixing) a therapeutically effective amount of the present compound witha pharmaceutically acceptable carrier or diluent.

A dose of the present invention is different depending on anadministration method, an age, a weight and condition of a patient, anda kind of a disease and, usually, in the case of oral administration,about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg may beadministered per adult a day, if necessary, by dividing the dose. Inaddition, in the case of parenteral administration, about 0.01 mg to1000 mg, preferably about 0.05 mg to 500 mg is administered per adult aday.

Examples are shown below.

Example A-19-Hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrid[1,2-a]pyrazine-7-carboxylicacid 4-fluoro-banzylamide Example B-19-Hydroxy-2-(2-methoxy-ethyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrid[1,2-a]pyrazine-7-carboxylicacid 4-fluoro-benzylamide

1) Mantol 1 (189 g, 1.5 mol) was dissolved in dimethylformamide (1890ml), and benzyl bromide (184 ml, 1.5 mol) was added. After the solutionwas stirred at 80° C. for 15 minutes, potassium carbonate (228 g, 1.65mol) was added, and the mixture was stirred for 1 hour. After thereaction solution was cooled to room temperature, an inorganic salt wasfiltered, and the filtrate was distilled off under reduced pressure. Tothe again precipitated inorganic salt was added tetrahydrofuran (1000ml), this was filtered, and the filtrate was distilled off under reducedpressure to obtain the crude product (329 g, >100%) of3-benzyloxy-2-methyl-pyran-4-one 2 as a brown oil. NMR (CDCl₃) δ: 2.09(3H, s), 5.15 (2H, s), 6.36 (1H, d, J=5.6 Hz), 7.29-7.41 (5H, m), 7.60(1H, d, J=5.6 Hz).

2) The compound 2 (162.2 g, 750 mmol) was dissolved in ethanol (487 ml),and aqueous ammonia (28%, 974 ml) and a 6N aqueous sodium hydroxidesolution (150 ml, 900 mmol) were added. After the reaction solution wasstirred at 90° C. for 1 hour, this was cooled to under ice-cooling, andammonium chloride (58 g, 1080 mmol) was added. To the reaction solutionwas added chloroform, this was extracted, and the organic layer waswashed with an aqueous saturated sodium bicarbonate solution, and driedwith anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, isopropyl alcohol and diethyl ether were added to theresidue, and precipitated crystals were filtered to obtain3-benzyloxy-2-methyl-1H-pyridine-4-one 3 (69.1 g, 48%) as a pale yellowcrystal.

NMR (DMSO-d₆) δ: 2.05 (3H, s), 5.04 (2H, s), 6.14 (1H, d, J=7.0 Hz),7.31-7.42 (5H, m), 7.46 (1H, d, J=7.2 Hz), 11.29 (1H, brs).

3) The above compound 3 (129 g, 599 mmol) was suspended in acetonitrile(1300 ml), and N-bromosuccinic acid imide (117 g, 659 mmol) was added,followed by stirring at room temperature for 90 minutes. Precipitatedcrystals were filtered, and washed with acetonitrile and diethyl etherto obtain 3-benzyloxy-5-bromo-2-methyl-pyridine-4-ol 4 (154 g, 88%) as acolorless crystal.

NMR (DMSO-d₆) δ: 2.06 (3H, s), 5.04 (2H, s), 7.32-7.42 (5H, m), 8.03(1H, d, J=5.5 Hz), 11.82 (1H, brs).

4) To a solution of the compound 4 (88 g, 300 mmol), palladium acetate(13.4 g, 60 mmol) and 1,3-bis(diphenylphosphino)propane (30.8 g, 516mmol) in dimethylformamide (660 ml) wore added methanol (264 ml) andtriethylamine (210 ml, 1.5 mol) at room temperature. The interior of areaction vessel was replaced with carbon monoxide, and the material wasstirred at room temperature for 30 minutes, and stirred at 80 degree for18 hours. A vessel to which ethyl acetate (1500 ml), an aqueoussaturated ammonium chloride solution (1500 ml) and water (1500 ml) hadbeen added was stirred under ice-cooling, and the reaction solution wasadded thereto. Precipitates were filtered, and washed with water (300ml), ethyl acetate (300 ml) and diethyl ether (300 ml) to obtain5-benzyloxy-4-hydroxy-6-methyl-nicotinic acid methyl eater 5 (44.9 g,55%) as a colorless crystal.

NMR (DMSO-d₆) δ: 2.06 (3H, s), 8.72 (3H, s), 5.02 (2H, s), 7.33-7.42(5H, m), 8.07 (1H, s).

5) After a solution of the compound 5 (19.1 g, 70 mmol) in aceticanhydride (184 ml) was stirred at 130° C. for 40 minutes, the solventwas distilled off under reduced pressure to obtain4-acetoxy-5-benzyloxy-6-methyl-nicotinic acid methyl ester 6 (19.9 g,90%) as a flesh colored crystal.

NMR (CDCl₃) δ: 2.29 (3H, s), 2.52 (3H, s), 3.89 (3H, s), 4.98 (2H, s),7.36-7.41 (5H, m), 8.85 (1H, s).

6) To a solution of the compound 6 (46.2 g, 147 mmol) in chloroform (370ml) was added metachloroperbenzoic acid (65%) (42.8 g, 161 mmol) inportions under ice-cooling, and this was stirred at room temperature for90 minutes. To the reaction solution was added a 10% aqueous potassiumcarbonate solution, and this was stirred for 10 minutes, followed byextraction with chloroform. The organic layer was washed withsuccessively with a 10% aqueous potassium carbonate solution, an aqueoussaturated ammonium chloride solution, and an aqueous saturated sodiumchloride solution, and dried with anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue was washedwith diisopropyl ether to obtain4-acetoxy-5-benzyloxy-6-methyl-1-oxy-nicotinic acid methyl eater 7 (42.6g, 87%) as a colorless crystal.

NMR (CDCl₃) δ: 2.30 (3H, s), 2.41 (3H, s), 3.90 (3H, s), 5.02 (2H, s),7.37-7.39 (5H, m), 8.70 (1H, s).

7) To acetic anhydride (500 ml) which had been heated to stir at 130° C.was added the compound 7 (42.6 g, 129 mmol) over 2 minutes, and this wasstirred for 20 minutes. The solvent was distilled off under reducedpressure to obtain 4-acetoxy-6-acetoxymethyl-6-benzyloxy-nicotinic acidmethyl ester 8 (49.6 g, >100%) as a black oil.

NMR (CDCl₃) δ: 2.10 (3H, s), 2.28 (3H, s), 3.91 (3H, s), 5.07 (2H, s),5.20 (2H, s), 7.35-7.41 (5H, m), 8.94 (1H, s).

8) To a solution of the compound 8 (46.8 g, 125 mmol) in methanol (140ml) was added a 2N aqueous sodium hydroxide solution (376 ml) underice-cooling, and this was stirred at 50° C. for 40 minutes. To thereaction solution were added diethyl ether and 2N hydrochloric acidunder ice-cooling, and precipitated crystals were filtered.

Resulting crystals were washed with water and diethyl ether to obtain5-benzyloxy-4-hydroxy-6-hydroxymethyl-nicotinic acid 9 (23.3 g, 68%) asa colorless crystal.

NMR (DMSO-d₆) δ: 4.49 (2H, s), 5.19 (2H, S), 5.85 (1H, brs), 7.14-7.20(2H, m), 7.33-7.43 (7H, m), 8.30 (1H, s), 10.73 (1H, t, J=5.8 Hz), 11.96(1H, brs).

9) To a solution of the compound 9 (131 g, 475 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (219 g, 1140mmol) and 1-hydroxybenzotriazole (128 g, 950 mmol) in dimethylformamide(1300 ml) was added 4-fluorobenzylamine (109 ml, 950 mmol), and this wasstirred at 80° C. for 1.5 hours. After the reaction solution was cooledto room temperature, hydrochloric acid was added, followed by extractionwith ethyl acetate. The extract was washed with a 5% aqueous potassiumcarbonate solution, an aqueous saturated ammonium chloride solution, andan aqueous saturated sodium chloride solution, and dried with anhydroussodium sulfate. The solvent was distilled off under reduced pressure toobtain a mixture (175 g) of 10 and 11, the resulting mixture wasdissolved in acetic acid (1050 ml) and water (1050 ml), and zinc (31.1g, 475 mmol) was added, followed by heating to reflux for 1 hour. Afterthe reaction solution was cooled to room temperature, a 10% aqueouspotassium carbonate solution was added, followed by extraction withethyl acetate. The extract was washed with an aqueous saturated ammoniumchloride solution, and an aqueous saturated sodium chloride solution,and dried with anhydrous sodium sulfate. After the solvent was distilledoff under reduced pressure, this was washed with diethyl ether to obtain5-benzyloxy-N-(4-fluoro-benzyl)-4-hydroxy-6-hydroxymethyl-nicotinic acidamide 10 (107 g, 59%) as a colorless crystal.

NMR (DMSO-d₆) δ: 4.45 (2H, d, J=4.8 Hz), 4.52 (2H, d, J=5.8 Hz), 5.09(2H, s), 6.01 (1H, brs), 7.36-7.43 (5H, m), 8.31 (1H, s), 12.63 (1H,brs).

10) After manganese dioxide (49 g) was added to a suspension of thecompound 10 (9.8 g, 25.6 mmol) in chloroform (490 ml), the mixture wasstirred at room temperature for 1 hour. After the reaction solution wasstirred at 60° C. for 20 minutes, Celite filtration was performed, andthis was washed with chloroform heated at 50° C. The filtrate wasdistilled off under reduced pressure to obtain5-benzyloxy-N-(4-fluoro-benzyl)-6-formyl-4-hydroxy-nicotinic acid amide12 (8.2 g, 84%) as a pale yellow crystal.

NMR (DMSO-d₆) δ: 4.53 (2H, d, J=5.8 Hz), 5.38 (2H, s), 7.15-7.21 (2H,m), 7.35-7.46 (7H, m), 8.33 (1H, s), 9.90 (1H, s), 10.35 (1H, t, J=5.8Hz), 12.49 (1H, brs).

11) To an aqueous solution (105 ml) of sodium chlorite (7.13 g, 78.8mmol), and sulfamic acid (7.65 g, 78.8 mmol) was added a solution of thecompound 12 (15.0 g, 39.4 mmol) in tetrahydrofuran (630 ml) underice-cooling, and the mixture was stirred at room temperature for 1 hour.After water (2500 ml) was added to the reaction solution, precipitatedcrystals were filtered. Washing with diethyl ether afforded3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylicacid 13 (14.0 g, 90%) as a colorless crystal.

NMR (DMSO-d₆) δ: 4.52 (2H, d, J=5.8 Hz), 5.13 (2H, s), 7.14-7.19 (2H,m), 7.31-7.40 (5H, m), 7.47-7.49 (2H, m), 8.31 (1H, d, J=4.5 Hz), 10.44(1H, t, J=5.9 Hz), 12.47 (1H, brs).

12) A solution of the compound 13 (198 mg, 0.500 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg,0.600 mmol) and 1-hydroxybenzotriazole (81 mg, 0.600 mmol) indimethylformamide (3 ml) was stirred at room temperature for 1.5 hours.Then, methanol (3 ml) and triethylamine (153 ul, 1.10 mmol) were added,and the mixture was heated to reflux for 1.5 hours. The reactionsolution was diluted with ethyl acetate, washed with an aqueoussaturated sodium bicarbonate solution, a 10% aqueous citric acidsolution, and an aqueous saturated sodium chloride solution, and driedwith anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was washed with diethyl ether toobtain3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylicacid methyl ester 14 (141 mg, 60%) as a colorless crystal.

NMR (DMSO-d₆) δ: 3.85 (3H, s), 4.52 (2H, d, J=6.0 Hz), 5.15 (2H, s),7.18-7.21 (2H, m), 7.31-7.47 (7H, m), 8.33 (1H, s), 10.41 (1H, t, J=6.0Hz), 12.50 (1H, brs).

13) After 3-bromopropene (2.15 ml, 24.8 mmol) was added to a solution ofthe compound 14 (6.79 g, 16.5 mmol), and cesium carbonate (8.09 g, 24.8mmol) in dimethylformamide (54 ml), the mixture was stirred at roomtemperature for 4.5 hours. To the reaction solution was added an aqueousammonium chloride solution, and this was extracted with ethyl acetate,washed with water and an aqueous saturated sodium chloride solution, anddried with anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was washed with diethyl ether toobtain 1-allyl-S-benzyloxy-5-(4-fluoro-benzylcarbamoyl)4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methyl ester 15 (6.15 g,83%) as a colorless crystal.

NMR (CDCl₃) δ: 3.76 (3H, s), 4.54 (2H, d, J=6.0 Hz), 4.60 (2H, d, J=6.0Hz), 5.20-5.37 (2H, m), 5.25 (2H, s), 5.80-5.93 (1H, m), 6.98-7.04 (2H,m), 7.31-7.35 (7H, m), 8.45 (1H, s), 10.41 (1H, m).

14) To a solution of the compound 15 (7.6 g, 16.9 mmol) in 1,4-dioxane(228 ml) was added an aqueous solution (38 ml) of potassium osmatedihydrate (372 mg, 1.01 mmol), and sodium metaperiodate (14.5 g, 67.6mmol) was further added, followed by stirring at room temperature for 2hours. The reaction solution was added to a vessel to which ethylacetate (300 ml) and water (300 ml) had been added, while stirring. Theorganic layer was washed with water, a 5% aqueous sodium hydrogensulfite solution and an aqueous saturated sodium chloride solution, anddried with anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was washed with diethyl ether toobtain3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-oxo-1-(2-oxo-ethyl)-1,4-dihydro-pyridine-2-carboxylicacid methyl ester 16 (5.39 g, 71%) as a colorless crystal.

NMR (CDCl₃) δ: 3.74 (3H, s), 4.60 (2H, d, J=5.0 Hz), 4.87 (2H, s), 5.27(2H, s), 6.98-7.04 (2H, m), 7.30-7.40 (7H, m), 8.39 (1H, s), 9.58 (1H,s), 10.38 (1H, s).

15) To a solution of the compound 16 (400 mg, 0.884 mmol) in methylenechloride (12 ml) were added 2-methoxyethylamine (77 ul, 0.884 mmol) andacetic acid (18 ul), and the mixture was stirred at room temperature for5 minutes. Thereafter, the reaction was performed at 140° C. for 30minutes in a microwave reaction apparatus. The solvent was distilled offunder reduced pressure, the residue was subjected to silica gel columnchromatography, and fractions eluting with toluene-acetone wereconcentrated under reduced pressure to obtain9-benzyloxy-2-(2-methy-ethyl)-1,8-dioxo-1,8-dihydro-2H-pyrid[1,2-a]pyrazine-7-carboxylicacid 4-fluoro-benzylamide 17-1 (226 mg, 54%) as a yellow solid.

NMR (CDCl₃) δ: 3.35 (3H, s), 3.65 (2H, t, J=5.1 Hz), 3.97 (2H, t, J=4.5Hz), 4.68 (2H, d, J=5.7 Hz), 5.28 (2H, s), 6.56 (2H, m), 7.01 (2H, t,J=8.7 Hz), 7.38-7.80 (5H, m), 7.65 (2H, d, J=6.6 Hz), 10.63 (1H, s).

16) To the compound 17-1 (140 mg, 0.293 mmol) was added trifluoroaceticacid (1.4 ml) under ice-cooling, and the mixture was stirred at 0° C.for 5 minutes and, then, at room temperature for 1.5 hours. The solventwas distilled off under reduced pressure, and this was diluted withchloroform, and added to ice water. This was washed with an aqueoussaturated sodium bicarbonate solution, a 10% aqueous citric acidsolution and water, and dried with anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue wasrecrystallized with methylene chloride-ethanol to obtain Example A-1 (89mg, 79%) as a yellow crystal.

melting point: 223-224° C.

NMR (DMSO-d₆) δ: 3.25 (3H, s), 3.58 (2H, t, J=5.4 Hz), 3.92 (2H, t,J=5.1 Hz), 4.53 (2H, d, J=5.7 Hz), 6.87 (1H, d, 6.3 Hz), 7.14 (2H, t,J=9.0 Hz), 7.33-7.38 (2H, nm), 7.47 (1H, d, J=6.0 Hz), 8.77 (1H, s),10.56 (1H, t, J=6.0 Hz), 12.00 (1H, brs).

17) The compound 17-1 (157 mg, 0.329 mmol) was dissolved indimethylformamide (18 ml) and methanol (1 ml), 10% palladium-carbonpowder (81 mg) was added, and the mixture was stirred at roomtemperature for 20 hours under the hydrogen atmosphere. The reactionsolution was filtered with Celite, and the filtrate was concentratedunder reduced pressure. The residue was dissolved in chloroform, thiswas filtered with Celite again, and the filtrate was concentrated underreduced pressure. The residue was recrystallized with methylenechloride-methanol to obtain Example B-1 (66 mg, 52%) as a brown crystal.

melting point: 197-199° C.

NMR (DMSO-d₆) δ: 3.27 (3H, s), 3.55 (2H, t, J=5.1 Hz), 3.68 (2H, t,J=5.1 Hz), 3.79 (2H, s), 4.36 (2H, s), 4.51 (2H, d, J=5.7 Hz), 7.15 (2H,t, J=8.7 Hz), 7.32-7.37 (2H, m), 8.38 (1H, s), 10.46 (1H, t, J=5.4 Hz),12.41 (1H, s).

Example C-1

1) A compound 33 was synthesized using 1-aminomethylcyclopentanolhydroxyethylamine according to the method of synthesizing a compound17-1.

1H-NMR (CDCl₃) δ: 1.30-1.80 (10H, m), 3.47 (1H, d, J=11.4 Hz), 3.61 (1H,d, J=11.4 Hz), 3.80-3.95 (1H, m), 4.30 (1H, dd, J=14.7, 3.0 Hz), 4.60(2H, d, J=56.7 Hz), 5.17-5.23 (2H, m), 5.39 (1H, d, J=9.9 Hz), 6.95-7.10(2H, m), 7.20-7.40 (5H, m), 7.58 (2H, d, J=7.2 Hz), 8.41 (1H, s), 10.40(1H, s).

2) A compound 33-2 was synthesized using hydroxyethylamine according tothe similar method.

Compound 33-2)5-Benzyloxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1-oxa-3a,8a-diaza-cyclopenta[b]naphthalene-7-carboxylicacid 4-fluorobenzylamide

1H-NMR (DMSO-d₆) δ: 3.48-3.58 (1H, m), 3.73-3.86 (1H, m), 3.97-4.10 (2H,m), 4.20-4.30 (1H, m), 4.46-4.60 (2H, m), 4.85 (1H, dd, J=12.3, 3.5 Hz),5.40 (1H, d, J=10.2 Hz), 5.18 (1H, d, J=10.2 Hz), 5.28 (1H, dd, J=10.2,3.2 Hz), 7.10-7.20 (2H, m), 7.23-7.40 (5H, m), 7.60-7.73 (2H, m), 8.60(1H, s), 10.22 (1H, m).

3) Example C-1 was synthesized using a compound 33, according to themethod of synthesizing Example A-1.

Melting point: >300° C.

1H-NMR (DMSO-d₆) δ: 1.10-1.60 (10H, m), 3.25 (1H, d, J=11.4 Hz), 3.37(1H, d, J=11.4 Hz), 3.76 (1H, t, J=10.5 Hz), 4.30 (2H, d, J=5.8 Hz),4.66 (1H, dd, J=12.2, 3.8 Hz), 5.22 (1H, dd, J=3.8, 10.4 Hz), 6.90-6.96(2H, m), 7.10-7.16 (2H, m), 8.25 (1H, s), 10.10 (1H, brs), 11.32 (1H,brs).

The following compounds were synthesized using the similar method.

Example C-25-Hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1-oxa-3a,8a-diaza-cyclopenta[b]naphthalene-7-carboxylicacid 4-fluorobenzylamide

Melting point: 272-274° C.

1H-NMR (DMSO-d₆) δ: 3.59-3.67 (1H, m), 3.72-3.81 (1H, m), 3.98-4.10 (2H,m), 4.27-4.35 (1H, m), 4.52 (2H, d, J=7.2 Hz), 4.92 (1H, dd, J=12.3,12.3 Hz), 5.27 (1H, dd, J=3.6, 9.9 Hz), 7.11-7.20 (2H, m), 7.30-7.40(2H, m), 8.49 (1H, s), 10.32 (1H, t, J=5.6 Hz), 11.53 (1H, s).

Example C-35-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 259° C.

1H-NMR (DMSO-d₆) δ: 1.60-1.67 (1H, m), 1.72-1.85 (1H, m), 3.25 (1H, td,J=12.8, 3.5 Hz), 3.86-3.93 (1H, m), 4.06 (1H, dd, J=11.4, 4.2 Hz),4.44-4.57 (5H, m), 5.28 (1H, t, J=3.8 Hz), 7.13-7.18 (2H, m), 7.33-7.37(2H, m), 8.51 (1H, s), 10.36 (1H, t, J=6.0 Hz), 12.47 (1H, s).

Example C-45-Hydroxy-1-isopropyl-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triaza-cyclopenta[b]naphthalene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 232-234° C.

NMR (DMSO-d₆) δ: 1.03 (3H, d, 6.6 Hz), 1.14 (3H, d, 6.6 Hz), 2.79-3.66(5H, m), 3.82 (1H, t, 10.8 Hz), 4.51 (3H, m), 4.90 (1H, m), 7.15 (2H, t,9.0 Hz), 7.34 (2H, m), 8.45 (1H, s), 10.39 (1H, t, 5.4 Hz), 11.60 (1H,s).

Example C-55-Hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triaza-cyclopenta[b]naphthalene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 256-258° C.

NMR (DMSO-d₆) δ: 3.00-3.55 (5H, m), 3.96 (1H, t, 11.4 Hz), 4.52 (2H, d,11.7 Hz), 4.76 (2H, m), 7.16 (2H, t, 8.7 Hz), 7.35 (2H, m), 8.48 (1H,s), 10.42 (1H, t, 5.4 Hz), 11.91 (1H, s).

Example C-65-Hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 255° C.

NMR (DMSO-d₆) δ: 1.60 (1H, s), 2.75-3.16 (4H, m), 4.52 (2H, d, 6.0 Hz),4.13-4.68 (4H, m), 7.16 (2H, 9.0 Hz, t), 7.34 (2H, m), 10.42 (1H, s),10.44 (1H, 6.0 Hz, t), 12.81 (1H, s).

Example C-71-(2-Diethylamino-ethyl)-5-hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-11-1,3a,8a-triaza-cyclopenta[b]naphthalene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 186-187° C.

NMR (DMSO-d₆) δ: 0.97 (6H, t, 7.2 Hz), 2.42-2.91 (10H, m), 3.44-3.87(5H, m), 4.23 (1H, m), 4.51 (2H, d, 5.7 Hz), 5.00 (1H, m), 7.16 (2H, t,9.0 Hz), 7.33-7.37 (2H, m), 8.43 (1H, s), 10.39 (1H, t, 5.7 Hz), 11.81(1H, s).

Example C-81-Hydroxy-2,11-dioxo-2,5,5a,7,8,9,10,11-octahydro-6-oxa-4a,10a-diaza-cyclohepta[b]naphthalene-3-carboxylicacid 4-fluoro-benzylamide

melting point: 242-244° C.

NMR (DMSO-d₆) δ: 1.40-2.00 (4H, m), 3.20-3.30 (1H, m), 3.66-3.77 (2H,m), 4.14-4.23 (1H, m), 4.38-4.41 (1H, m), 4.52 (2H, d, 6.3 Hz),4.58-4.63 (1H, m), 5.34 (1H, brs), 7.15 (2H, t, 9.0 Hz), 7.33-7.37 (2H,m), 8.50 (1H, s), 10.39 (1H, brs), 12.14 (1H, s).

Example C-95-Hydroxy-1-(2-hydroxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

NMR (DMSO-d₆) δ: 1.58-1.80 (1H, m), 2.70-3.60 (7H, m), 4.40-4.54 (6H,m), 4.77-4.82 (1H, m), 7.15 (2H, t, 9.0 Hz), 7.33-7.38 (2H, m), 8.52(1H, s), 10.43 (1H, brs), 12.57 (1H, s).

Example C-10 1-Hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylic acid4-fluoro-benzylamide

melting point: 256° C.

NMR (DMSO-d₆) δ: 1.47-1.77 (4H, m), 2.60-2.81 (2H, m), 3.34-3.41 (1H,m), 4.08-4.12 (1H, m), 4.26-4.40 (2H, m), 4.52 (2H, d, J=6.0 Hz), 7.15(2H, t, 8.8 Hz), 7.33-7.36 (2H, m), 8.43 (1H, s), 10.46 (1H, t, J=6.0Hz), 12.68 (1H, s).

Example C-115-Hydroxy-1-(2-methoxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 147° C.

NMR (DMSO-d₆) δ: 1.56-1.74 (2H, m), 2.53-2.58 (1H, m), 2.66-3.10 (4H,m), 3.18 (3H, s), 3.41-3.39 (2H, m), 4.37-4.52 (5H, m), 4.73-4.80 (1H,m), 7.15 (2H, t, 8.8 Hz), 7.33-7.37 (2H, m), 8.56 (1H, s), 10.40 (1H, t,J=6.0 Hz), 12.62 (1H, s).

Example C-125-Hydroxy-1-(2-isopropoxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 151° C.

NMR (DMSO-d₆) δ: 1.02 (6H, dd, J=4.0, 6.0 Hz), 1.56-1.67 (2H, m),2.53-2.58 (1H, m), 2.74-3.04 (4H, m), 3.18 (3H, s), 3.41-3.52 (3H, m),4.41-4.59 (5H, m), 4.79-4.83 (1H, m), 7.15 (2H, t, 8.8 Hz), 7.34-7.36(2H, m), 8.58 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.56 (1H, s).

Example C-135-Hydroxy-3,3-dimethyl-6,10dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 275-277° C.

NMR (DMSO-d₆) δ: 2.97 (3H, s), 3.01 (3H, s), 3.00-3.18 (3H, m),4.45-4.56 (5H, m), 5.16 (1H, s), 7.15 (2H, t, J=9 Hz), 7.35 (2H, dd,J=5.4 Hz, 8.7 Hz), 8.51 (1H, s), 10.36 (1H, t, J=5.7 Hz), 12.4 (1H, s).

Example C-141-Cyclohexyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid-4-fluoro-benzylamide

melting point: 275-277° C.

NMR (DMSO-d₆) δ: 1.22-1.70 (2H, m), 2.50-3.02 (3H, m), 4.45 (4H, m),4.52 (2H, s), 4.78 (1H, d, J=13.2 Hz), 7.16 (2H, t, J=8.7 Hz), 7.35 (2H,dd, J=5.7 Hz, 8.4 Hz), 8.62 (1H, s), 10.52 (1H, s), 12.55 (1H, s).

Example C-155-Hydroxy-1-isopropyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid-4-fluoro-benzylamide

melting point: 220° C.

NMR (DMSO-d₆) δ: 0.94 (6H, d, J=9.6 Hz), 1.53-1.67 (2H, m), 2.92-3.30(3H, m), 4.32-4.40 (4H, m), 4.62 (2H, d, J=5.7 Hz), 4.89 (1H, d, J=14.1Hz), 7.16 (2H, t, J=9.0 Hz), 7.35 (2H, dd, J=6.3 Hz, 9.0 Hz), 8.61 (1H,s), 10.46 (1H, s), 12.55 (1H, s).

Example C-165-Hydroxy-3,3-dimethyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 280° C.

NMR (DMSO-d₆) δ: 0.87 (3H, s), 0.93 (3H, s), 2.59-3.15 (6H, m),4.09-4.57 (6H, m), 7.14 (2H, d, J=9.0 Hz), 7.34 (2H, dd, J=5.4 Hz, 8.41Hz), 8.42 (1H, s), 10.46 (1H, s), 12.77 (1H, s).

Example C-175-Hydroxy-1-(2-morpholin-4-yl-2-oxa-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 140° C.

NMR (DMSO-d₆) δ: 1.60 (2H, m), 2.91-3.62 (13H, m), 4.41 (2H, m), 4.51(2H, d, J=4.8 Hz), 4.80 (2H, m), 7.15 (2H, t, J=8.7 Hz), 7.34 (2H, m),8.44 (1H, s), 10.43 (1H, s), 12.54 (1H, s).

Example C-181-(3-Acetylamino-propyl)-5hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluor-benzylamide

melting point: 177-178° C.

NMR (DMSO-d₆) δ: 1.74 (3H, s), 1.40-2.98 (1H, m), 3.60 (1H, s),4.25-4.65 (7H, m), 7.14 (2H, t, J=8.4 Hz), 7.34 (2H, m), 7.71 (1H, s),8.26 (1H, s), 10.60 (1H, s).

Example C-191-Dimethycarbamoylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 190° C.

NMR (DMSO-d₆) δ: 1.60 (2H, m), 2.76 (3H, s), 2.83 (3H, s), 2.90-3.59(5H, s), 4.40 (2H, m), m), 8.54 (1H, s), 10.42 (1H, s).

Example C-205-Hydroxy-1-(3-methanesulfonylamino-propyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 176° C.

NMR (DMSO-d₆) δ: 1.54-1.75 (4H, m), 2.80 (3H, s), 2.30-3.04 (3H, m),4.45 (2H, m), 4.52 (2H, d, J=5.6 Hz), 4.75 (1H, d, J=13.2 Hz), 6.91 (1H,t, J=5.6 Hz), 7.16 (2H, t, J=8.8 Hz), 7.36 (2H, m), 8.61 (1H, 6), 10.41(1H, t, J=5.6 Hz), 12.58 (1H, s).

Example C-215-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-dizazaanthracene-7-carboxylicacid 4-fluorobenzylamide

NMR (CDCl3) δ: 1.27 (3H, d, J=6.0 Hz), 1.55-1.78 (2H, m), 3.11 (1H, td,J=12.9, 8.7 Hz), 3.89-4.00 (1H, m), 4.16 (1H, dd, J=13.8, 3.0 Hz), 4.34(1H, dd, J=13.8, 3.9 Hz), 4.60 (2H, d, J=6.0 Hz), 4.71 (1H, ddd, J=13.5,4.8, 1.8 Hz), 5.08 (1H, t, J=3.9 Hz), 6.96-7.04 (2H, m), 7.26-7.35 (2H,m), 8.82 (1H, s), 10.41 (1H, br s), 12.41 (1H, br s).

Example F-15-Hydroxy-1-isobutyl-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triazacyclopenta[b]naphthalene-7-carboxylicacid-4-fluorobenzamide

1) According to the method of synthesizing a compound 17-1, the crudepurified product (503 mg) of a compound 48 was obtained at a yield of82% from a compound 16 (600 mg).

2) To a solution of a compound 48 (100 mg, 0.22 mmol), isobutylaldehyde(39 μl, 0.432 mmol) and acetic acid (25 μl, 0.432 mmol) indichloromethane (4 ml) was added sodium triacetoxyborohydride (92 mg,0.432 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 2 hours. Further, isobutylaldehyde (20 μl) and sodiumtriacetoxyborohydride (46 mg) wore added, and the mixture was stirredfor 30 minutes. To the reaction solution was added water, this wasextracted with chloroform, and the organic layer was washed with anaqueous saturated sodium bicarbonate solution. After drying, the solventwas distilled off under reduced pressure, and this was purified bysilica gel column chromatography. A compound 49 (87 mg) was obtained asa colorless crystal at a yield of 78%.

1H-NMR (CDCl₃) δ: 0.96 (3H, d, J=6.6 Hz), 0.97 (3H, d, J=6.3 Hz),1.72-1.86 (1H, m), 2.25-2.41 (2H, m), 2.47-2.58 (1H, m), 3.39-3.46 (1H,m), 3.69-3.76 (2H, m), 3.85-3.93 (1H, m), 4.06 (1H, dd, J=9.9, 2.7 Hz),4.16-4.22 (1H, m), 4.57 (1H, dd, J=15.3, 5.1 Hz), 4.64 (1H, dd, J=14.7,5.1 Hz), 5.20 (1H, d, J=9.9 Hz), 5.38 (1H, d, J=9.9 Hz), 6.96-7.05 (2H,m), 7.28-7.36 (5H, m), 7.58-7.62 (2H, m), 8.40 (1H, s), 10.44 (1H, brs),

3) According to the method of a step 17) of Example B-1, a compound F-1(43 mg) was obtained at a yield of 64% from a compound 49 (81 mg).

1H-NMR (DMSO-d₆) δ: 0.90 (3H, d, J=6.4 Hz), 0.91 (3H, d, J=6.0 Hz),1.75-1.84 (1H, m), 2.24-2.39 (1H, m), 2.39-2.54 (2H, m), 3.36-3.43 (1H,m), 3.52-3.60 (1H, m), 3.67-3.73 (1H, m), 3.81-3.88 (1H, m), 4.19-4.23(1H, m), 4.52 (2H, d, J=6.0 Hz), 4.94-4.99 (1H, m), 7.12-7.20 (2H, m),7.32-7.38 (2H, m), 8.45 (1H, s), 10.37 (1H, t, J=2.0 Hz), 11.74 (1H, s).

According to the same manner as that of Example F-1, the followingExample compounds F-2 to F-63 were synthesized.

Example F-25-Hydroxy-1-isobutyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 146-148° C.

1H-NMR (DMSO-d₆) δ: 0.63 (3H, d, J=6.6 Hz), 0.70 (3H, d, J=6.6 Hz),1.56-1.66 (2H, m), 1.67-1.75 (1H, m), 1.94-1.99 (1H, m), 2.41-2.54 (2H,m), 2.96-3.06 (2H, m), 4.41-4.59 (5H, m), 4.76-4.81 (1H, m), 7.14-7.21(21H, m), 7.33-7.38 (2H, m), 8.61 (1H, s), 10.40 (1H, d, J=5.8 Hz),12.56 (1H, s).

Example F-31-Cyclopropylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 182-184° C.

NMR (DMSO-d₆) δ: 0.06 (2H, m), 0.43 (2H, d, 8.4 Hz), 0.80 (1H, m), 1.66(2H, m), 2.28-3.30 (4H, m), 4.40-4.50 (4H, m), 4.62 (2H, d, 6.0 Hz),4.78 (2H, m), 7.15 (2H, t, 8.7 Hz), 7.84 (2H, m), 8.55 (1H, s), 10.47(1H, s), 12.55 (1H, e).

Example F-41-Cyclopentylmethyl-5-hydroxy-6,1-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 184-185° C.

NMR (DMSO-d₆) δ: 0.88-2.10 (1H, m), 2.60 (2H, m), 2.95-3.28 (2H, m),4.38-4.53 (6H, m), 4.82 (1H, m), 7.15 (2H, t, 9.0 Hz), 7.34 (2H, m),8.57 (1H, s), 10.42 (1H, s), 12.45 (1H, s).

Example F-55-Hydroxy-1-(4-methylsulfanylbenzyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(DMSO-d₆) δ: 1.51-1.56 (1H, m), 1.69-1.74 (1H, m), 2.42 (3H, s),2.55-2.62 (1H, m), 2.80-2.84 (1H, m), 3.00-3.08 (1H, m), 3.32-3.36 (1H,m), 3.93 (1H, d, J=13.6 Hz), 4.45-4.53 (4H, m), 4.58 (1H, s), 4.83 (1H,d, J=15.2 Hz), 7.11-7.19 (6H, m), 7.33-7.40 (2H, m), 8.34 (1H, s), 10.38(1H, t, J=6.0 Hz), 12.58 (1H, s).

Example F-61-(5-Chloro-1,3-dimethyl-1H-pyrazol-4-ylmethyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(DMSO-d₆) δ: 1.56-1.59 (2H, m), 1.88 (3H, s), 2.37-2.45 (1H, m),2.76-2.80 (1H, m), 3.00-3.06 (2H, m), 3.64 (3H, s), 3.87 (1H, d, J=13.2Hz), 4.40-4.55 (51H, m), 4.97 (1H, d, J=14.4 Hz), 7.13-7.10 (2H, m),7.33-7.38 (2H, m), 8.56 (1H, s), 10.39 (1H, t, J=6.0 Hz), 12.46 (1H, s).

Example F-75-Hydroxy-1-(3-methoxybenzyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(DMSO-d₆) δ: 1.52-1.57 (1H, m), 1.70-1.80 (1H, m), 2.60-2.68 (1H, m),2.84-2.90 (1H, m), 3.01-3.09 (1H, m), 3.36 (1H, d, J=14.0 Hz), 3.61 (3H,s), 3.91 (1H, d, J=14.0 Hz), 4.45-4.52 (4H, m), 4.58 (1H, s), 4.76 (1H,d, J=14.0 Hz), 6.68-6.73 (2H, m), 6.77 (1H, d, J=7.6 Hz), 7.13-7.19 (3H,m), 7.33-7.38 (2H, m), 8.17 (1H, s), 10.38 (1H, t, J=6.0 Hz), 12.57 (1H,s).

Example F-85-Hydroxy-1-(4-methanesulfonybenzyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(DMSO-d₆) δ: 1.54-1.58 (1H, m), 1.74-1.80 (1H, m), 2.67-1.74 (1H, m),2.83-2.87 (1H, m), 3.05-3.12 (1H, m) 3.18 (3H, s), 3.52 (1H, d, J=14.8Hz), 4.09 (1H, d, J=14.8 Hz), 4.46-4.52 (4H, m), 4.67 (1H, s), 4.73 (1H,d, J=14.8 Hz), 7.12-7.18 (2H, m), 7.32-7.36 (2H, m), 7.46 (2H, m), 7.80(2H, d, J=8.0 Hz), 8.17 (1H, s), 10.37 (1H, t, J=5.8 Hz), 12.59 (1H, s).

Example F-95-Hydroxy-1-(6-methoxypyridin-3-ylmethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(DMSO-d₆) δ: 1.51-1.56 (1H, m), 1.71-1.77 (1H, m), 2.58-2.66 (1H, m),2.80-2.86 (1H, m), 3.01-3.09 (1H, m), 3.38 (1H, d, J=13.6 Hz), 3.78 (3H,s), 3.87 (1H, d, J=13.6 Hz), 4.45-4.52 (4H, m), 4.60 (1H, s), 4.82 (1H,d, J=13.6 Hz), 6.71 (1H, d, J=8.6 Hz), 7.12-7.19 (2H, m), 7.33-7.38 (2H,m), 7.49 (1H, d, J=8.6 Hz), 7.98 (1H, s), 8.30 (1H, s), 10.37 (1H, t,J=6.0 Hz), 12.58 (1H, s).

Example F-105-Hydroxy-1-isobutyl-3,3-dimethyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(DMSO-d₆) δ: 0.64 (3H, d, J=6.4 Hz); 0.82 (3H, d, J=6.8 Hz), 0.90 (3H,s), 0.91 (3H, s), 1.59-1.67 (1H, m), 1.92-1.97 (1H, m), 2.11-2.15 (1H,m), 2.51-2.57 (1H, m), 2.67 (1H, d, J=12.0 Hz), 2.77 (1H, d, J=12.8 Hz),4.13 (1H, s), 4.21 (1H, d, J=12.8 Hz), 4.47-4.59 (3H, s), 4.80 (1H, dd,J=14.4, 2.8 Hz), 7.14-7.19 (2H, m), 7.34-7.38 (2H, m), 8.66 (1H, s),10.41 (1H, t, J=6.0 Hz), 12.44 (1H, s).

Example F-115-Hydroxy-1,3,3-trimethyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(DMSO-d₆) δ: 0.89 (6H, s), 2.14-2.18 (1H, m), 2.24 (3H, s), 2.54-2.58(1H, m), 2.74-2.78 (1H, s), 3.88 (1H, s), 4.21 (1H, d, J=13.2 Hz),4.45-4.53 (3H, m), 4.72-4.76 (1H, m), 7.13-7.19 (2H, m), 7.33-7.38 (2H,m), 8.64 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.46 (1H, s).

Example F-124-[7-(4-Fluorobenzylcarbamoyl)-5-hydroxy-6,10-dioxy-3,4,6,9,9a,10-hexahydro-2H-1,4a,8a-triazaanthracene-1-yl]butanoicacid ethyl eater

(CDCl3) δ: 1.23 (3H, t, J=7.1 Hz), 1.70-1.79 (1H, m), 1.86-2.00 (1H, m),2.17-2.34 (2H, m), 2.46-2.57 (1H, m), 2.61-2.77 (2H, m), 2.85-2.92 (1H,m), 3.13-3.18 (1H, m), 4.13 (2H, q, J=7.1 Hz), 4.27-4.34 (2H, m),4.67-4.63 (3H, m), 4.66-4.73 (1H, m), 6.05-7.03 (2H, m), 7.29-7.36 (2H,m), 8.36 (1H, s), 10.48 (1H, t, J=4.8 Hz), 12.50 (1H, s).

Example F-131-(3-Dimethylcarbamoylpropyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracen-7-carboxylicacid 4-fluorobenzylamide

(CDCl₃) δ: 1.62-1.82 (3H, m), 1.83-2.00 (1H, m), 2.10-2.35 (2H, m),2.57-2.65 (2H, m), 2.75-2.95 (2H, m), 2.92 (3H, s), 2.96 (3H, s),3.07-3.14 (11H, m), 4.23-4.30 (2H, m), 4.60 (2H, d, J=6.0 Hz), 4.68 (1H,dd, J=13.2, 4.5 Hz), 5.12 (1H, d, J=12.6 Hz), 6.95-7.02 (2H, m),7.28-7.35 (2H, m), 8.42 (1H, s), 1054 (1H, t, J=5.4 Hz), 12.51 (1H, s).

Example F-145-Hydroxyl-(4-morpholin-4-yl-4-oxobutyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(CDCl₃) δ: 1.61-1.83 (3H, m), 1.84-2.00 (1H, m), 2.12-2.23 (1H, m),2.26-2.36 (1H, m), 2.56-2.64 (2H, m), 2.76-2.95 (2H, m), 3.09-3.15 (1H,m), 3.87 (2H, t, J=4.8 Hz), 3.61-3.86 (6H, m), 4.26-4.32 (2H, m), 4.59(2H, d, J=5.7 Hz), 4.68 (1H, dd, J=13.2, 4.5 Hz), 4.96-5.01 (1H, m),6.96-7.03 (2H, m), 7.28-7.35 (2:1, m), 8.40 (1H, 8), 10.52 (1H, t, J=5.7Hz), 12.51 (1H, s).

Example F-155-Hydroxy-1-methyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 252-253° C.

(DMSO-d₆) δ: 1.56-1.75 (2H, m), 2.22 (3H, s), 2.50-2.55 (1H, m),2.90-3.10 (2H, m), 4.17 (1H, brs), 4.39-4.42 (2H, m), 4.52 (2H, d, J=6.0Hz), 4.74-4.78 (1H, m), 7.13-7.17 (2H, m), 7.33-7.37 (2H, m), 8.61 (1H,s), 10.40 (1H, t, J=6.0 Hz), 12.54 (1H, s).

Example F-165-Hydroxy-6,10-dioxo-1-thiophen-3-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 242-243° C.

(DMSO-d₆) δ: 1.62-1.73 (2H, m), 2.59-2.62 (1H, m), 2.87-3.03 (2H, m),3.52 (1H, d, J=13.6 Hz), 3.90 (1H, d, J=14.4 Hz), 4.40-4.56 (6H, m),4.83-4.90 (1H, m), 6.92 (1H, d, J=0.2 Hz), 7.13-7.17 (2H, m), 7.28-7.37(3H, m), 7.42-7.44 (1H, m), 8.46 (1H, s), 10.39 (1H, t, J=6.0 Hz), 12.58(1H, s).

Example F-175-Hydroxy-6,10-dioxo-1-thiazol-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylic acid 4-fluorobenzylamide

melting point 214-215° C.

(DMSO-d₆) δ: 1.54-1.72 (2H, m), 2.75-2.81 (1H, m), 2.05-3.07 (2H, m),3.80 (1H, d, J=16.0 Hz), 4.37 (1H, d, J=16.4 Hz), 4.44-4.51 (4H, m),4.69 (1H, brs), 4.89-4.93 (1H, m), 8.37 (1H, s), 10.36 (1H, t, J=6.0Hz), 12.50 (1H, s).

Example F-185-Hydroxy-(3-methylsulfanyl-propyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 162.164° C.

(DMSO-d₆) δ: 1.50-1.82 (4H, m), 2.27 (3H, s), 2.32-2.44 (3H, m),2.60-2.82 (2H, m), 3.00-3.14 (2H, m), 4.37-4.59 (5H, m), 4.75-4.79 (1H,m), 7.13-7.17 (2H, m), 7.33-7.35 (2H, m), 8.60 (1H, s), 10.40 (1H, t,J=6.0 Hz), 12.57 (1H, s).

Example F-195-Hydroxy-6,10-dioxo-1-pyridin-4-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 180-183° C.

(DMSO-d₆) δ: 1.52-1.76 (2H, m), 2.62-2.80 (2H, m), 3.01-3.07 (1H, m),3.42 (1H, d, J=6.0 Hz), 12.55 (1H, s).

Example F-201-Cyclohexylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 201-202° C.

(DMSO-d₆) δ: 0.56-0.59 (1H, m), 0.87-0.84 (1H, m), 1.02-1.13 (3H, m),1.23-1.29 (1H, m), 1.49-1.70 (6H, m), 1.92-1.97 (1H, m), 2.62-2.55 (1H,m), 2.96-3.03 (2H, m), 4.40-4.43 (3H, m), 4.62 (2H, d, J=6.0 Hz),4.73-4.77 (1H, m), 7.12-7.16 (2H, m), 7.32-7.36 (2H, m), 8.59 (1H, s),10.40 (1H, t, J=5.2 Hz), 12.58 (1H, s).

Example F-215-Hydroxy-6,10-dioxo-1-pyridin-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 216-219° C.

(DMSO-d₆) δ: 1.52-1.76 (2H, m), 2.66-2.80 (1H, m), 2.90-3.07 (2H, m),3.67 (1H, d. J=1.2 Hz), 4.01 (1H, d, J=13.2 Hz), 4.37-4.97 (4H, m), 4.62(1H, brs), 4.85-4.88 (1H, m), 7.07-7.25 (4H, m), 7.33-7.36 (2H, m),7.64-7.68 (1H, m), 8.26 (1H, s), 8.45 (1H, s), 10.36 (1H, t, J=6.0 Hz),12.57 (1H, s).

Example F-221-(2-Ethyl-butyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 137-140° C.

(DMSO-d₆) δ: 0.62 (3H, t, J=7.2 Hz), 0.77 (3H, t, J=7.2 Hz), 0.09-1.30(5H, m), 1.57-1.71 (2H, m), 1.97-2.02 (1H, m), 2.44-2.58 (2H, m),3.02-3.32 (2H, m), 4.34-4.57 (5H, m), 4.78-4.82 (1H, m), 7.13-7.17 (2H,m), 7.32-7.36 (2H, m), 8.60 (1H, s), 10.39 (1H, t, J=(0.2 Hz), 12.54(1H, s).

Example F-285-Hydroxy-1-(2-morpholin-4ylethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 264-256° C.

(DMSO-d₆) δ: 1.55-1.68 (2H, m), 2.28-2.39 (3H, m), 2.59-2.65 (1H, m),2.82-3.09 (3H, m), 7.12-7.17 (2H, m), 7.32-7.36 (2H, m), 8.52 (1H, s),10.45 (1H, t, J=5.2 Hz), 12.55 (1H, s).

Example F-241-Hydroxy-6-methyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-6H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylic acid 4-fluorobenzylamide

melting point: 255° C.

(DMSO-d₆) δ: 1.48-1.55 (1H, m), 1.67-1.80 (3H, m), 2.29 (3H, s),2.75-2.80 (2H, m), 3.23-8.31 (1H, m), 4.07-4.09 (1H, m), 4.36-4.40 (1H,m), 4.45-4.59 (3H, m), 4.68-4.69 (1H, m), 7.13-7.17 (2H, m), 7.30-7.37(2H, m), 8.50 (1H, s), 10.42 (1H, t, J=6.0 Hz), 12.42 (1H, s).

Example F-251-Hydroxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 4-fluorobenzylamide

melting point: 221.223° C.

DMSO-d₆) δ: 0.81 (3H, d, J=6.8 Hz), 0.84 (3H, d, J=6.4 Hz), 1.45-1.78(5H, m), 2.36-2.54 (214, m), 2.27-2.93 (2H, m), 3.17-3.23 (1H, m),4.03-4.06 (1H, m), 4.32-4.56 (4H, m), 4.82-4.85 (1H, m), 7.13-7.17 (2H,m), 7.30-7.37 (2H, m), 8.48 (1H, s), 10.42 (1H, t, J=6.0 Hz), 12.53 (1H,s).

Example F-266-Cyclopropylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 4-fluorobenzylamide

melting point: 213° C.

DMSO-d₆) δ: 0.15-0.26 (2H, m), 0.46-0.48 (2H, m), 0.86-1.06 (1H, m),1.45-1.75 (4H, m), 2.45-2.65 (1H, m), 2.68-2.83 (1H, m), 2.91-2.98 (2H,m), 3.17-3.26 (1H, m), 4.08-4.14 (1H, m), 4.43-4.45 (2H, m), 4.54 (2H,d, J=5.6 Hz), 4.89-4.91 (1H, m), 7.15-7.19 (2H, m), 7.35-7.30 (2H, m),8.50 (1H, s), 10.47 (1H, t, J=6.0 Hz), 12.52 (1H, s).

Example F-271-Furan-2-ylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 193-197° C.

DMSO-d₆) δ: 1.67 (2H, m), 2.61 (1H, s), 2.93 (2H, m), 3.75 (1H, d,J=14.8 Hz), 3.84 (1H, d, J=14.8 Hz), 4.34-4.47 (3H, m), 4.62 (2H, d,J=6.0 Hz), 4.96 (1H, d, J=14.8 Hz), 6.86 (2H, s), 7.16 (2H, t, J=8.8Hz), 7.85 (2H, m), 7.59 (1H, s), 8.07 (1H, s), 10.43 (1H, s), 12.51 (1H,s).

Example F-281-(4-Dimethylamino-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 221-223° C.

DMSO-d₆) δ: 1.55-1.99 (2H, m), 2.87 (6H, s), 2.87-3.06 (4H, m), 3.80(1H, d, J=14.0 Hz), 7.15 (2H, t, J=8.8 Hz), 7.35 (2H, m), 8.31 (1H, s),10.39 (1H, s), 12.58 (1H, s).

Example F-295-Hydroxy-6,10-dioxo-1-(4-trifluoromethyl-benzyl)-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 273-277° C.

DMSO-d₆) δ: 1.52-1.70 (2H, m), 2.63-3.04 (3H, m), 3.50 (1H, d, J=14.8Hz), 4.10 (1H, d, J=14.8 Hz), 4.64 (5H, m), 4.79 (1H, d, J=14.8 Hz),7.14 (2H, t, J=8.8 Hz), 7.33 (2H, m), 7.55 (2H, d, J=6.8 Hz), 7.61 (2H,d, J=8.0 Hz), 8.22 (1H, s), 10.40 (1H, s), 12.56 (1H, s).

Example F-305-Hydroxy-6,10-dioxo-1-pyridin-3-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 210-212° C.

DMSO-d₆) δ: 1.51-1.76 (2H, m), 2.63 (1H, t, J=12.8 Hz), 2.80 (1H, d,J=12.0 Hz), 8.07 (1H, t, J=12.8 Hz), 3.44 (1H, d, J=13.2 Hz), 4.00 (1H,d, 14.0 Hz), 4.47 (4H, m), 4.62 (1H, s), 4.84 (1H, d, J=14.0 Hz), 7.16(2H, t, J=8.8 Hz), 7.33 (2H, m), 7.58 (1H, d, J=7.6 Hz), 8.30 (1H, s),8.45 (2H, s), 10.41 (1H, s), 12.57 (1H, s).

Example F-311-(2-Chloro-6-fluoro-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylic acid 4-fluorobenzylamide

melting point: 213-215° C.

DMSO-d₆) δ: 1.58 (2H, 2H), 2.55-3.09 (3H, m), 3.45 (1H, d, J=12.4 Hz),4.16 (1H, d, J=12.4 Hz), 4.40-4.58 (4H, m), 5.12 (1H, d, J=14.4 Hz),7.15-7.38 (7H, m), 8.66 (1H, s), 10.41 (1H, t, J=6.4 Hz), 1.2.46 (1H,s).

Example F-325-Hydroxy-1-(4-methoxy-benzyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 191-193° C.

NMR (DMSO-d₆) δ: 1.50-1.77 (2H, m), 2.58-3.06 (3H, m), 3.68 (3H, s),3.88 (1H, d, J=13.6 Hz), 4.41-4.56 (4H, m), 4.80 (2H, d, J=14.4 Hz),6.80 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.4 Hz), 7.15 (2H, t, J=8.8 Hz),7.35 (2H, m), 8.28 (1H, s), 10.48 (1H, s), 12.58 (1H, s).

Example F-331-(3,5-Bis-trifluoromethyl-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 275-277° C.

NMR (DMSO-d₆) δ: 1.58-1.88 (2H, m), 2.51-3.14 (3H, m), 3.33-4.10 (3H,m), 4.51 (2H, m), 4.73 (1H, m), 7.15 (2H, m), 7.34 (2H, m), 7.82-7.93(4H, m), 10.31 (1H, s), 12.57 (1H, s).

Example F-341-(4-Diethylamino-benzyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluorobenzylamide

melting point: 182° C.

NMR (DMSO-d₆) δ: 1.04 (6H, t, J=6.8 Hz), 1.50-1.69 (2H, m), 2.55-3.05(3H, m), 8.26 (4H, q, J=7.2 Hz), 3.80 (1H, d, J=13.6 Hz), 4.44-4.57 (4H,m), 4.91 (1H, d, J=12.4 Hz), 6.52 (2H, d, J=8.8 Hz), 6.04 (2H, d, J=8.4Hz), 7.15 (2H, t, J=8.4 Hz), 7.35 (2H, m), 8.46 (1H, s), 10.41 (1H, s),12.60 (1H, s).

Example F-355-Hydroxy-1-((E)-2-methyl-but-2-enyl)-6,1-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 175-177° C.

NMR (DMSO-d₆) δ: 1.35 (3H, s), 1.51 (3H, d, J=6.0 Hz), 1.52-1.69 (3H,m), 2.60-3.15 (3H, m), 4.31-4.52 (5H, m), 4.67-4.76 (1H, m), 5.30-5.40(1H, m), 7.15 (2H, t, J=8.4 Hz), 7.28-43 (2H, m), 8.46 (1H, s), 10.39(1H, brs), 12.60 (1H, s).

Example F-361-(3-Dimethylamino-2-methyl-propyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

NMR (DMSO-d₆) δ: 0.63-0.68 (2H, m), 1.57-1.82 (1H, m), 2.11-2.49 (10H,m), 2.98-3.11 (2H, m), 4.41-4.54 (5H, m), 4.73-4.80 (1H, m), 7.14-7.18(2H, m), 7.31-7.38 (2H, m), 8.58 (1H, s), 10.40 (1H, s), 12.57 (1H, s).

Example F-371-(3,3-Dimethyl-butyl)-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 175-177° C.

NMR (DMSO-d₆) δ: 1.19-1.36 (2H, m), 1.57-1.70 (2H, m), 2.23-2.30 (1H,m), 2.51-2.60 (2H, m), 2.97-3.04 (2H, m), 4.42-4.54 ((5H, m), 4.78 (1H,d, J=14.0 Hz), 7.13-7.17 (2H, m), 7.83-7.36 (2H, m), 8.63 (1H, s), 10.39(1H, t, J=6.0 Hz), 12.56 (1H, s).

Example F-381-Ethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 221° C.

NMR (DMSO-d₆) δ: 0.94 (3H, t, J=6.8 Hz), 1.56-1.71 (2H, m), 2.45-2.50(1H, m), 2.59-2.76 (2H, m), 2.96-3.03 (2H, m), 4.40-4.44 (3H, m), 4.52(2H, d, J=6.0 Hz), 4.77-4.82 (1H, m), 7.14-7.18 (2H, m), 7.34-7.38 (2H,m), 8.62 (1H, s), 10.41 (1H, t, J=6.0 Hz), 12.59 (1H, s).

Example F-395-Hydroxy-6,10-dioxo-1-(2-oxo-propyl)-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 244-246° C.

NMR (DMSO-d₆) δ: 1.54-1.61 (1H, m), 1.67-1.76 (1H, m), 2.22 (3H, s),2.50-2.56 (1H, m), 2.91-3.02 (2H, m), 4.18 (1H, s), 4.38-4.45 (2H, m),4.52 (2H, d, J=6.0 Hz), 4.76 (1H, d, J=14.4 Hz), 7.13-7.18 (2H, m),7.34-7.37 (2H, m), 8.61 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.64 (1H, s).

Example F-405-Hydroxy-6,10-dioxo-1-(4,4,4-trifluoro-butyl)-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 220° C.

NMR (DMSO-d₆) δ: 1.53-1.62 (2H, m), 1.67-1.75 (1H, m), 2.07-2.18 (2H,m), 2.40-2.47 (1H, m), 2.64-2.78 (2H, m), 2.96-3.04 (2H, m), 4.42-4.49(2H, m), 4.53 (2H, d, J=5.2 Hz), 4.74 (1H, d, J=12.8 Hz), 7.13-7.17 (2H,m), 7.33-7.37 (2H, m), 8.61 (1H, s), 10.40 (1H, t, J=6.0 Hz), 12.57 (1H,s).

Example F-415-Hydroxy-1-(3-methyl-butyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 151° C.

NMR (DMSO-d₆) δ: 0.78 (6H, dd, J=7.6, 16.2 Hz), 1.21-1.28 (2H, m),1.41-1.48 (1H, m), 1.66-1.71 (2H, m), 2.22-2.31 (1H, m), 2.51-2.59 (1H,m), 2.66-2.73 (1H, m), 2.96-3.06 (2H, m), 4.41-4.55 (5H, m), 4.80 (1H,d, J=13.2 Hz), 7.13-7.18 (2H, m), 7.33-7.37 (2H, m), 8.64 (1H, s), 10.40(1H, t, 3=6.0 Hz), 12.57 (1H, s).

Example F-425-Hydroxy-1-isobutyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 8-chloro-2-fluoro-benzylamide

melting point: 180-182° C.

NMR (DMSO-d₆) δ: 0.62 (3H, d, J=6.0 Hz), 0.78 (3H, d, J=6.4 Hz),1.55-1.69 (31H, m), 1.93-1.99 (1H, m), 2.97-3.08 (2H, m), 4.39-4.46 (3H,m), 4.59-4.64 (2H, m), 4.75-4.81 (1H, m), 7.16-7.23 (1H, m), 7.27-7.34(1H, m), 7.47-7.53 (1H, m), 8.50 (1H, s), 10.44 (1H, s), 12.57 (1H, s).

Example F-431-Cyclopropylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 189-192° C.

NMR (DMSO-d₆) δ: 0.00-0.10 (2H, m), 0.36-0.41 (2H, m), 0.70-0.77 (1H,m), 1.57-1.69 (2H, m), 2.62-2.65 (1H, m), 2.67-2.85 (1H, m), 2.91-2.99(1H, m), 4.30-4.41 (2H, m), 4.48-4.52 (2H, m), 4.71-4.80 (1H, m),7.06-7.10 (1H, m), 7.18-7.22 (1H, m), 7.36-7.40 (1H, m), 8.52 (1H, s),10.30 (1H, s), 12.26 (1H, s).

Example F-441-Furan-2-ylmethyl-1-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 190-192° C.

NMR (DMSO-d₆) δ: 1.56-1.68 (2H, m), 2.54-2.63 (1H, m), 2.89-2.99 (2H,m), 3.80 (2H, dd, J=18.4, 33.2 Hz), 4.37-4.51 (3H, m), 4.62 (2H, d,J=6.0 Hz), 4.07 (1H, d, J=15.2 Hz), 6.39 (2H, s), 7.18-7.22 (1H, m),7.31-7.34 (1H, m), 7.48-7.51 (1H, m), 7.58 (1H, s), 8.64 (1H,

Example F-455-Hydroxy-6,10-dioxo-1-thiazol-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 217-210° C.

NMR (DMSO-d₆) δ: 1.59-1.74 (2H, m), 2.76-2.83 (1H, m), 2.97-3.08 (2H,m), 3.90 (1H, d, J=16.0 Hz), 4.36 (1H, d, J=16.0 Hz), 4.45-4.69 (5H,nm), 4.89 (1H, d, J=14.8 Hz), 7.18-7.22 (1H, m), 7.28-7.31 (1H, m),7.47-7.53 (1H, m), 7.54 (1H, d, J=3.2 Hz), 7.68 (1H, d, J=3.2 Hz), 8.34(1H, s), 10.40 (1H, d, J=6.0 Hz), 12.52 (1H, s).

Example F-465-Hydroxy-6,10-dioxo-1-pyridin-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 190-193° C.

NMR (DMSO-d₆) δ: 1.54-1.61 (1H, m), 1.69-1.75 (1H, m), 2.66-2.74 (1H,m), 2.91-3.08 (2H, m), 3.68 (1H, d, J=14.4 Hz), 4.02 (1H, d, J=14.8 Hz),4.40-4.67 (5H, m), 4.85 (1H, d, J=12.4 Hz), 7.16-7.35 (3H, m), 7.46-7.52(1H, m), 7.61-7.69 (1H, m), 8.20 (1H, s), 8.43-8.47 (1H, m), 10.41 (1H,d, J=6.0 Hz), 12.58 (1H, s).

Example F-475-Hydroxy-1-isobutyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

melting point: 194° C.

NMR (DMSO-d₆) δ: 0.62 (3H, d, J=6.4 Hz), 0.78 (3H, d, J=6.4 Hz),1.55-1.69 (3H, m), 1.93-1.99 (1H, m), 2.97-3.08 (2H, m), 4.39-4.46 (3H,m), 4.50-4.59 (2H, m), 4.77 (1H, d, 10.39 (1H, s), 12.56 (1H, s).

Example F-481-Cyclopropylmethyl-5-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

melting point: 169-171° C.

NMR (DMSO-d₆) δ: 0.00-0.10 (2H, m), 0.42-0.44 (2H, m), 0.77-0.81 (1H,m), 1.59-1.74 (2H, m), 2.27-2.32 (1H, m), 2.62-2.72 (1H, m), 3.05-3.12(1H, m), 4.30-4.58 (5H, m), 4.69 (1H, d, J=14.8 Hz), 7.03-7.11 (1H, m),7.22-7.26 (1H, m), 7.37-7.40 (1H, m), 8.62 (1H, s), 10.40 (1H, t, J=6.0Hz), 12.57 (1H, s).

Example F-491-Furan-2-ylmethyl-6-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

melting point: 186-188° C.

NMR (DMSO-d₆) δ: 1.56-1.68 (2H, m), 2.55-2.64 (1H, m), 2.88-2.99 (2H,m), 3.80 (2H, dd, J=15.6, 34.8 Hz), 4.36-4.56 (5H, m), 4.97 (1H, d,J=16.0 Hz), 6.39 (2H, s), 7.05-7.08 (1H, m), 7.21-7.26 (1H, m),7.37-7.44 (1H, m), 7.58 (1H, s), 8.64 (1H, s), 10.38 (1H, t, J=5.6 Hz),12.53 (1H, s).

Example F-505-Hydroxy-6,10-dioxo-1-thiazol-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

melting point: 168-170° C.

NMR (DMSO-d₆) δ: 1.59-1.74 (2H, m), 2.76-2.83 (1H, m), 2.97-3.08 (2H,m), 3.89 (1H, d, J=16.4 Hz), 4.36 (1H, d, J=3=16.0 Hz), 4.44-4.55 (4H,m), 4.69 (1H, s), 4.89 (1H, d, J=14.8 Hz), 7.03-7.09 (1H, m), 7.20-7.27(1H, m), 7.34-7.41 (1H, m), 7.54 (1H, d, J=3.2 Hz), 7.68 (1H, d, J=3.2Hz), 8.34 (1H, s), 10.35 (1H, d, J=6.0 Hz), 12.50 (1H, s).

Example F-515-Hydroxy-6,10-dioxo-1-pyridin-2-ylmethyl-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7carboxylicacid 2,4-difluoro-benzylamide

melting point: 200-203° C.

NMR (DMSO-d₆) δ: 1.54-1.61 (1H, m), 1.69-1.78 (1H, m), 2.71-2.79 (1H,m), 2.91-3.09 (2H, m), 3.72 (1H, d, J=14.4 Hz), 4.07 (1H, d, J=14.4 Hz),4.44-4.54 (4H, m), 4.70 (1H, s), 4.82 (1H, d, J=14.4 Hz), 7.04-7.10 (1H,m), 7.21-7.42 (4H, m), 7.74-7.80 (1H, m), 8.17 (1H, a), 8.47-8.49 (1H,m), 10.35 (1H, d, J=6.0 Hz), 12.57 (1H, s).

Example F-521-Hydroxy-6-methyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 230-231° C.

NMR (DMSO-d) δ: 1.47-1.53 (1H, m), 1.62-1.78 (3H, m), 2.29 (3H, s),2.77-2.81 (2H, m), 4.05-4.10 (1H, m), 4.35-4.40 (1H, m), 4.54-4.64 (3H,m), 4.70 (1H, s), 7.18-7.22 (1H, m), 7.30-7.34 (1H, m), 7.47-7.52 (1H,m), 8.49 (1H, s), 10.47 (1H, d, J=6.0 Hz), 12.44 (1H, s).

Example F-531-Hydroxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 215-216° C.

NMR (DMSO-d₆) δ: 0.83 (6H, dd, J=6.8, 13.6 Hz), 1.45-1.80 (5H, m),2.36-2.41 (1H, m), 2.77-2.93 (2H, m), 3.17-3.24 (1H, m), 4.02-4.09 (1H,m), 4.32-4.40 (2H, m), 4.61 (2H, d, J=5.6 Hz), 4.82-4.84 (1H, m),7.18-7.22 (1H, m), 7.30-7.33 (1H, m), 7.48-7.51 (1H, m), 8.47 (1H, s),10.48 (1H, t, J=6.0 Hz), 12.55 (1H, s).

Example F-546-Cyclopropylmethyl-1-hydroxy-2,11-dioxo-2,6a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 212° C.

NMR (DMSO-d₆) δ: 0.00-0.10 (2H, m), 0.40-45 (2H, m), 0.80-0.87 (1H, m),1.45-1.77 (3H, m), 2.64-2.69 (1H, m), 2.85-2.95 (2H, m), 3.13-3.20 (1H,m), 4.03-4.09 (1H, m), 4.36-4.40 (2H, m), 4.59 (2H, d, J=5.6 Hz),4.84-4.86 (1H, m), 7.16-7.20 (1H, m), 7.28-7.32 (1H, m), 7.46-7.50 (1H,m), 8.45 (1H, s), 10.46 (1H, t, J=6.0 Hz), 12.50 (1H, s).

Example F-556-Furan-2-ylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3carboxylicacid 3-chloro-2-fluoro-benzylamide

Melting point: 189-190° C.

NMR (DMSO-d₆) δ: 1.48-1.63 (3H, m), 1.70-1.77 (1H, m), 2.79-2.83 (2H,m), 3.90 (2H, dd, J=14.8, 39.6 Hz), 4.06-4.11 (1H, m), 4.40-4.51 (2H,m), 4.61 (2H, d, J=6.6 Hz), 4.89-4.91 (1H, m), 6.30-6.33 (1H, m),6.38-6.40 (1H, m), 7.18-7.22 (1H, m), 7.30-7.34 (1H, m), 7.48-7.53 (1H,m), 7.57 (1H, s), 8.45 (1H, s), 10.45 (1H, t, J=6.0 Hz), 12.44 (1H, s).

Example F-561-Hydroxy-6-methyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 2,4-difluoro-benzylamide

melting point: 241° C.

NMR (DMSO-d₆) δ: 1.47-1.53 (1H, m), 1.62-1.78 (3H, m), 2.29 (3H, m),2.77-2.81 (2H, m), 4.05-4.10 (1H, m), 4.35-4.40 (1H, m), 4.53-4.61 (3H,m), 4.69 (1H, s), 7.03-7.08 (1H, m), 7.20-7.27 (1H, m), 7.37-7.43 (1H,m), 8.49 (1H, s), 10.42 (1H, d, J=6.0 Hz), 12.43 (1H, s).

Example F-571-Hydroxy-6-isobutyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 2,4-difluoro-benzylamide

melting point: 203° C.

NMR (DMSO-d₆) δ: 0.82 (6H, dd, J=6.4, 13.2 Hz), 1.45-1.80 (5H, m),2.36-2.42 (1H, m), 2.77-2.93 (2H, m), 3.15-3.23 (1H, m), 4.02-4.08 (1H,m), 4.32-4.41 (2H, m), 4.54 (2H, d, J=5.6 Hz), 4.82-4.84 (1H, m),7.02-7.09 (1H, m), 7.20-7.27 (1H, m), 7.36-7.43 (1H, m), 8.47 (1H, s),10.41 (1H, t, J=6.0 Hz), 12.54 (1H, s).

Example F-586-Cyclopropylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 2,4-difluoro-benzylamide

melting point: 182-183° C.

NMR (DMSO-d₆) δ: 0.00-0.10 (2H, m), 0.40-45 (2H, m), 0.80-0.87 (1H, m),1.43-1.77 (3H, m), 2.60-2.69 (1H, m), 2.85-2.95 (2H. n), 3.11-3.19 (1H,m), 4.00-4.06 (1H, m), 4.36-4.40 (2H, m), 4.51 (2H, d, J=5.6 Hz),4.83-4.87 (1H, m), 7.00-7.07 (1H, m), 7.16-7.23 (1H, m), 7.34-7.38 (1H,m), 8.44 (1H, s), 10.39 (1H, t, J=6.0 Hz), 12.47 (1H, s).

Example F-596-Furan-2-ylmethyl-1-hydroxy-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triaza-cyclohepta[b]naphthalene-3-carboxylicacid 2,4-difluoro-benzylamide

melting point: 171-173° C.

NMR (DMSO-d₆) δ: 1.47-1.64 (3H, m), 1.70-1.77 (1H, m), 2.79-2.83 (2H,m), 3.90 (2H, dd, J=15.6, 9.6 Hz), 4.05-4.11 (1H, m), 4.41-4.57 (4H, m),4.90-4.92 (1H, m), 6.30-6.33 (1H, m), 6.38-6.40 (1H, m), 7.03-7.09 (1H,m), 7.20-7.27 (1H, m), 7.37-7.45 (1H, m), 7.57 (1H, s), 8.44 (1H, s),10.41 (1H, t, J=6.0 Hz), 12.48 (1H, s).

Example F-605-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 276° C.

NMR (DMSO-d₆) δ: 1.60-1.68 (1H, m), 1.77-1.84 (1H, m), 3.85-3.93 (1H,m), 4.03-4.07 (1H, m), 4.43-4.62 (5H, m), 5.28 (1H, m), 7.17-7.22 (1H,m), 7.29-7.34 (1H, m), 7.47-7.52 (1H, m), 8.49 (1H, s), 10.41 (23H, d,J=6.0 Hz), 12.48 (1H, s).

Example F-615-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

melting point: 258° C.

NMR (DMSO-d₆) δ: 1.60-1.69 (1H, m), 1.77-1.85 (1H, m), 3.86-3.92 (1H,m), 4.04-4.08 (1H, m), 4.43-4.55 (5H, m), 5.28 (1H, s), 7.03-7.09 (1H,m), 7.21-7.27 (1H, m), 7.36-7.43 (1H, m), 8.50 (1H, s), 10.35 (0.1H, d,J=6.0 Hz), 12.47 (1H, s).

Example F-625-Hydroxy-1-(2-methoxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 3-chloro-2-fluoro-benzylamide

melting point: 193° C.

NMR (DMSO-d₆) δ: 1.53-1.73 (2H, m), 2.51-2.58 (1H, m), 2.71-2.78 (1H,m), 2.81-2.87 (1H, m), 2.95-3.08 (2H, m), 3.17 (3H, s), 4.40-4.52 (3H,m), 4.62 (1H, d, J=5.6 Hz), 4.78 (1H, d, J=14.4 Hz), 7.18-7.22 (1H, m),7.30-7.34 (1H, m), 7.47-7.52 (1H, m), 8.55 (1H, s), 10.45 (1H, d, J=6.0Hz), 12.59 (1H, s).

Example F-635-Hydroxy-1-(2-methoxy-ethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

melting point: 166-168° C.

NMR (DMSO-d₆) δ: 1.55-1.72 (2H, m), 2.51-2.58 (1H, m), 2.70-2.77 (1H,m), 2.80-2.87 (1H, m), 2.97-3.07 (2H, m), 3.18 (3H, s), 4.39-4.52 (3H,m), 4.54 (1H, d, J=5.2 Hz), 4.78 (1H, d, J=13.6 Hz), 7.03-7.09 (1H, m),7.20-7.27 (1H, m), 7.37-7.48 (1H, m), 8.55 (1H, a), 10.40 (1H, d, J=6.0Hz), 12.58 (1H, s).

Example F-645-Hydroxy-1-(1H-imidazol-4-ylmethyl)-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triazaanthracene-7-carboxylicacid 4-fluorobenzylamide

(DMSO-d₆) δ: 1.55-1.59 (1H, m), 1.64-1.70 (1H, m), 2.58-2.66 (1H, m),2.87-2.95 (2H, m), 3.67 (1H, d, J=15.2 Hz), 3.78 (1H, d, J=15.2 Hz),4.34 (1H, s), 4.38-4.43 (1H, m), 4.47-4.54 (3H, m), 5.05 (1H, d, J=14.0Hz), 7.00 (1H, s), 7.13-7.19 (2H, m), 7.33-7.38 (1H, m), 7.59 (1H, s),8.55 (1H, s), 10.41 (1H, t, J=5.6 Hz), 11.95 (1H, br s), 12.59 (1H, s).

Example H-11-Acetyl-5-hydroxy-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triaza-cyclopenta[b]naphthalene-7-carboxylicacid 4-fluoro-benzylamide

1) To a solution of a compound 48 (120 mg, 0.26 mmol) in methylenechloride (1.2 ml) were added triethylamine (43 μl, 0.31 mmol), aceticanhydride (29 μl, 0.31 mmol), and 4-dimethylaminopyridine (cat.) at roomtemperature, and the mixture was stirred for 30 minutes. Further,triethylamine (18 μl, 0.13 mmol) and acetic anhydride (12 μl, 0.13 mmol)were added, and the mixture was stirred for 4 hours. 2N hydrochloricacid was added, this was extracted with chloroform, and the organiclayer was washed with water, dried with sodium sulfate, and concentratedunder reduced pressure. Diisopropyl ether was added to crystallize thematerial, which was filtered to obtain 53 (112 mg) as a pale orangecrystal at a yield of 86%.

2) An Example compound H-1 (71 mg) was obtained at a yield of 82% from acompound 53 (1.06 mg), according to the method of Example B-1 17).

melting point 290° C.

NMR (DMSO-d₆) δ: 2.08 (3H, s), 3.44-4.21 (5H, m), 4.51 (2H, d, 5.7 Hz),4.93 (1H, m), 5.46-5.62 (1H, m), 7.15 (2H, t, 9.0 Hz), 7.84 (2H, m),8.49 (1H, s), 10.40 (1H, t, 5.7 Hz), 11.48 (1H, e).

An Example compound H-2 was synthesized according to the same manner asthat of Example H-1.

Example H-21-Acetyl-6-hydroxy-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 290° C.

NMR (DMSO-d₆) δ: 1.95 (2H, m), 2.14 (3H, s), 2.85 (2H, m), 4.45 (4H, m),4.51 (2H, d, 5.7 Hz), 5.99 (1H, s), 7.15 (2H, t, 9.0 Hz), 7.34 (2H, m),8.37 (1H, s), 10.46 (1H, s), 12.28 (1H, s).

Example I-15-Hydroxy-1-methanesulfonyl-4,6-dioxo-2,3,4,6,9,9a-hexahydro-1H-1,3a,8a-triaza-cyclopenta[b]naphthalene-7-carboxylicacid 4-fluoro-benzylamide

1) To a solution of a compound 48 (140 mg, 0.30 mmol) in pyridine (1.4ml) were added methanesulfonyl chloride (28 μl, 0.36 mmol), and4-dimethylaminopyridine (cat.) at room temperature, and the mixture wasstirred for 3 hours. After 2N hydrochloric acid was added, this wasextracted with ethyl acetate, and the organic layer was washed withwater, dried with sodium sulfate, and concentrated under reducedpressure. Diisopropylether was added to crystallize the material, whichwas filtered to obtain 54 (127 mg) as a pale orange crystal at a yieldof 78%.

2) According to the method of Example B-1 17), an Example compound I-1(21 mg) was obtained at a yield of 21% from a compound 54 (123 mg).

melting point: 260° C.

NMR (DMSO-d₆) δ: 3.16 (3H, s), 3.30-4.15 (5H, m), 4.45 (2H, d, 5.7 Hz),4.27 (2H, m), 5.36 (1H, m), 7.14 (2H, t, 8.7 Hz), 7.33 (2H, m), 8.22(1H, s), 10.53 (1H, s).

According to the same manner as that of Example I-1, an Example compound1-2 was synthesized.

Example I-25-Hydroxy-1-methanesulfonyl-6,10-dioxo-1,2,3,4,6,9,9a,10-octahydro-1,4a,8a-triaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

melting point: 257-259° C.

NMR (DMSO-d₆) δ: 1.80-1.96 (2H, m), 3.02-3.58 (2H, m), 3.16 (3H, s),4.76 (2H, m), 5.56 (1H, s), 7.16 (2H, t, 9.0 Hz), 7.365 (2H, m), 8.36(1H, s), 10.39 (1H, s).

Example L-15,9-Dihydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-1H-2-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

1) According to the method of synthesizing a compound 66, a compound 62(278 mg, 57%) was obtained from a compound 13 (357 mg).

2) According to the method of synthesizing a compound 57, a compound 63(202 mg, 70%) was obtained from a compound 62 (278 mg).

3) To a solution of a compound 63 (200 mg, 0.403 mmol) in chloroform (2ml) were added dimethyl sulfoxide (286 μl, 4.03 mmol), and triethylamine(337 μl, 2.42 mmol), the mixture was stirred for 10 minutes underice-cooling, a sulfur trioxide-pyridine complex (321 mg, 2.02 mmol) wasadded, and the mixture was stirred at room temperature for 2 hours. Tothe reaction solution was added water (3 ml), and chloroform wasdistilled off under reduced pressure, followed by extraction with ethylacetate. The organic layer was washed with water, dried with anhydroussodium sulfate, and the solvent was distilled off under reducedpressure. The crystalline residue was washed with ethyl acetate toobtain a compound 64 (60 mg) at a yield of 30%.

4) Using a compound 64, and according to the method of synthesizingExample A-1, an Example compound L-1 was synthesized.

NMR (DMSO-d₆) δ: 2.98-3.10 (1H, m), 3.38-3.60 (2H, m), 3.80-4.20 (5H,m), 4.40-4.55 (2H, m), 5.48 (1H, brs), 5.85 (1H, s), 7.15 (2H, t, J=8.4Hz), 7.33-7.37 (2H, m), 8.45 (1H, s), 8.60 (1H, s), 10.27-10.42 (1H, m),12.61 (1H, brs).

Example M-11-Hydroxy-2,10-dioxo-2,4b,5,6,7,8,9,10-octahydro-4a,9a-diaza-benzo[a]azulene-3-carboxylicacid 4-fluoro-benzylamide

1) According to the method of synthesizing a compound 21, a compound 65(207 mg) was obtained at a yield of 24% from a compound 18 (250 mg).

2) According to the method of synthesizing a compound 64, a compound 66(313 mg, 67%) was obtained from a compound 65 (470 mg).

3) After trifluoroacetic acid (10 ml) was added to a compound 66 (100mg, 0.020 mmol), the mixture was stirred at 75° C. for 4 hours. Thesolvent was distilled off under reduced pressure, and this was dilutedwith chloroform, and added to ice water. This was washed with an aqueoussaturated sodium bicarbonate solution, a 10% aqueous citric acidsolution, and water, and dried with anhydrous sodium sulfate, and thesolvent was distilled off under reduced pressure. The residue wassubjected to silica gel column chromatography, and fractions eluted withchloroform-methanol were concentrated under reduced pressure, andrecrystallized with ethyl acetate-diisopropyl ether to obtain an Examplecompound M-1 (23 mg, 16%).

melting point 281-283° C.

NMR (DMSO-d₆) δ: 1.48-1.52 (2H, m), 1.62-1.83 (3H, m), 2.04-2.18 (1H,m), 2.28-2.35 (1H, m), 4.08-4.16 (1H, m), 4.48-4.53 (2H, m), 5.58-5.61(1H, m), 7.11-7.20 (2H, m), 7.30-7.38 (2H, m), 8.29 (1H, s), 10.30-10.36(1H, m), 12.78 (1H, brs).

Example X-1(R)-6-Hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1,2-d]pyrazine-3-carboxylicacid 4-fluoro-benzylamide

1) Selenium dioxide (666 mg, 6.0 mmol) was added to the solution ofcompound 2 (216 mg, 1.0 mmol) in bromobenzene (2 ml). Then the mixturewas heated up to 160° C., and stirred for 16 h. After celite filtrationthe solvent was evaporate. The precipitate was purified by silicagelcolumn chromatography, and fractions eluting With n-hexan/EtOAc wereconcentrated under reduced pressure to obtain compound 100 (164 mg, 71%)as a yellow oil.

1H-NMR (CDCl₃) δ: 5.52 (1H, s), 6.50 (1H, d, J=6.0 Hz), 7.36 (5H, m),7.74 (1H, d, J=6.3 Hz), 9.88 (1H, s).

2) Sulfamic acid (1.50 g, 15.4 mmol) and NaClO₂ (1.05 g, 11.6 mmol) wasadded to the solution of compound 100 (2.54 g, 11.0 mmol) in acetone (20ml) and water (30 ml). Then the mixture was stirred for 3 h. The solventwas evaporated under reduced pressure to obtain compound 101 (2.18 mg,80%) as a white solid.

1H-NMR (DMSO-d₆) δ: 5.11 (2H, s), 6.55 (1H, d, J=5.4 Hz), 7.32-7.46 (5H,m), 8.21 (1H, d, J=5.7 Hz).

3) (R)-2-N-BOC-aminomethyl pyrrolidine (391 mg, 1.95 mmol) was added tothe solution of compound 101 (400 mg, 1.62 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (373 mg,1.95 mmol), and 1-hydroxybenzotriazole (219 mg, 1.62 mmol) in TH (6 ml).After attiring for 16 h NaHCO₃ aqueous solution was added to themixture. The mixture was extracted with EtOAc, which was washed withNH₄Cl aqueous solution and brine. The organic phase was dried overMgSO₄. After a filtration the solvent was removed under reduced pressureto obtain compound 102 (694 mg, 100%) as a white solid.

1H-NMR (CDCl₃) δ: 1.46 (9H, s), 1.56-2.14 (4H, m), 3.29 (4H, m), 4.18(1H, m), 5.24 (1H, s), 5.27 (1H, s), 6.46 (1H, d, J=5.7 Hz), 7.35 (5H,m), 7.69 (1H, d, J=5.7 Hz).

4) The solution of compound 102 (694 mg, 1.95 mmol) in HCl/EtOAc (4mol/l, 8 ml) was stirred for 30 min. The soluvant was removed underreduced pressure, diluted with EtOH (16 ml) then. A saturated NaHCO₃aqueous solution was added to the solution to control pH at D. Themixture was stirred at 50° C. for 2 h, then diluted with water. Themixture was extracted with CHCl₃, washed with brine, and dried overMgSO₄. The solvent was removed under reduced pressure to obtain compound103 (413 mg, 68%) as a yellow solid.

1H-NMR (CDCl₃) δ: 1.54-2.22 (4H, m), 3.60 (2H, m), 3.80 (1H, t, J=12.0Hz), 4.18 (1H, d, J=12.0 Hz), 5.15 (1H, d, J=0.9 Hz), 5.35 (1H, d, J=9.0Hz), 6.71 (1H, d, J=5.4 Hz), 7.33 (3H, m), 7.50 (1H, d, J=5.1 Hz), 7.63(2H, d, J=7.2 Hz).

5) NaOAc (118 mg, 1.44 mmol) and bromine (0.234 ml, 2.62 mmol) wereadded to the solution of compound 103 (408 mg, 1.31 mmol) in acetic acid(8 ml), stirred for 30 min then. An aqueous solution of NaOH (2M) wasadded to the mixture, and extracted with CH₃Cl₂, washed with brine, anddried over Na₃SO₄. The solvent was removed under reduced pressure togive compound 104 (390 mg, 77%) as a white solid.

1H-NMR (CDCl₃) δ: 1.55-2.19 (4H, m), 3.55-4.02 (5H, m), 5.12 (1H, d,J=0.6 Hz), 5.35 (1H, d, J=9.9 Hz), 7.29-7.38 (3H, m), 7.61 (1H, s), 7.67(2H, d, J=6.6 Hz).

6) Tetrakis triphenylphosphine paradium (0) (77 mg, 0.067 mmol) andN,N-diisopropylethylamine (0.29 ml, 1.67 mmol) were added to thesolution of compound 104 (130 mg, 0.334 mmol) in DMSO (2.6 ml). themixture was stirred under CO atmosphere for 2 h at 80° C. The reactionmixture was diluted with a saturated NH₄Cl aqueous solution, extractedwith EtOAc then. And the organic phase was washed with brine, and driedover Na₂SO₄. The precipitate was purified by silicagel columnchromatography, and fractions eluting with MeOH/EtOAc were concentratedunder reduced pressure to obtain compound 105 (115 mg, 76%) as a whiteoil.

1H-NMR (CDCl₃) δ: 1.56-2.33 (4H, m), 3.66 (2H, m), 3.90 (2H, m), 4.10(1H, s), 4.66 (2H, m), 5.20 (1H, d, J=9.9 Hz), 5.37 (1H, d, J=9.0 Hz),7.00 (2H, t, J=8.7 Hz), 7.33 (5H, m), 7.61 (2H, m), 8.39 (1H, m), 10.50(1H, s).

7) A mixture of compound 105 (111 mg, 0.241 mmol) and paradium-carbon(10%, 22 mg) in THF (8 ml) and MeOH (2 ml) was stirred under hydrogenatmosphere for 3 h. After celite filtration the solvent was removedunder reduced pressure to give the example X-1 (57 mg, 64%) as a whitesolid.

Melting point: 274° C.

1H-NMR (DMSO-d₆) δ: 1.56-2.25 (4H, m), 3.48-3.65 (2H, m), 4.01 (2H, m),4.51 (2H, d, J=5.7 Hz), 4.71 (1H, d, J=9.9 Hz), 7.14 (2H, t, J=9.0 Hz),7.33 (2H, dd, J=5.7, 8.7 Hz), 8.41 (1H, s), 10.44 (1H, t, J=6.0 Hz),12.18 (1H, s).

The following compounds were synthesized using the similar method.

Example X-2(R)-6-Hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1,2-d]pyrazine-3-carboxylicacid 2,4-difluoro-benzylamide

Melting point: 300° C.

1H-NMR (DMSO-d₆) δ: 1.03-2.20 (4H, m), 3.39-3.66 (2H, m), 4.02 (2H, m),4.54 (2H, d, J=6.0 Hz), 4.71 (1H, d, J=9.0 Hz), 7.06 (1H, m), 7.23 (1H,m), 7.38 (1H, m), 8.41 (1H, s), 10.43 (1H, t, J=6.0 Hz), 12.19 (1H, s).

Example X-3(R)-6-Hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1,2-d]pyrazine-3-carboxylicacid 3-chloro-2-fluoro-benzylamide

Melting point: 304° C.

1H-NMR (DMSO-d₆) δ: 3.44-3.66 (2H, m), 4.01 (2H, m), 4.61 (2H, d, J=5.4Hz), 4.70 (1H, d, J=9.0 Hz), 7.20 (1H, m), 7.31 (1H, m), 7.49 (1H, m),8.41 (1H, s), 10.49 (1H, t, J=5.7 Hz), 12.20 (1H, s).

Example X-41-Hydroxy-2,9-dioxo-2,5,6,7,8,9,10,10a-octahydro-4a,8a-diaza-anthracene-3-carboxylicacid 4-fluoro-benzylamide

Melting point: 259° C.

1H-NMR (DMSO-d₆) δ: 1.33-1.79 (6H, m), 2.51 (1H, m), 3.88 (1H, m), 4.12(1H, dd, J=0.3, 14.1 Hz), 4.38 (1H, d, J=12.9 Hz), 4.53 (3H, m), 7.16(2H, t, J=9.0 Hz), 7.34 (2H, dd, J=5.7, 8.7 Hz), 8.39 (1H, s), 10.44(1H, t, J=8.3 Hz), 12.84 (1H, s).

According to the same manner as that of Example C-21, the followingExample compounds Y-1 to Y-18 were synthesized.

Example Y-1(3S,9aS)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide Example Y-9(3R,9aR)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

1H-NMR (CDCl₃) δ: 0.90 (3H, d, J=6.9 Hz), 2.00-2.10 (1H, m), 2.70 (1H,dd, J=11.6, 13.4 Hz), 3.41 (1H, dd, J=11.2, 12.9 Hz), 4.05-4.45 (2H, m),4.30-4.38 (1H, dd, J=4.0, 14.1 Hz), 4.63 (2H, d, J=5.9 Hz), 4.65-4.75(1H, m), 4.98 (1H, t, J=3.7 Hz), 6.80-6.84 (2H, m), 7.32-7.40 (1H, m),8.31 (1H, s), 10.38 (1H, brs), 12.37 (1H, s).

Example Y-2(4S,9aR)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-banzylamide Example Y-3(4R,9aS)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

1H-NMR (CDCl₃) δ: 1.42 (3H, d, J=7.0 Hz), 1.56 (1H, dd, J=2.0, 14.0 Hz),2.19-2.30 (1H, m), 4.02 (1H, d, J=2.2 Hz), 4.05 (1H, t, J=2.3 Hz), 4.12(1H, dd, J=6.0, 13.6 Hz), 4.27 (1H, dd, J=4.2, 13.4 Hz), 4.64 (2H, d,J=6.9 Hz), 4.95-5.05 (1H, m), 5.26 (2H, d, J=4.1, 5.8 Hz), 6.76-6.85(2H, m), 7.30-7.40 (1H, m), 8.30 (1H, s), 10.38 (1H, brs), 12.45 (1H,s).

Example Y-4(2R,9aR)-5-Hydroxy-2-methoxymethyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide Example Y-8(2S,9aS)-5-Hydroxy-2-methoxymethyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

1H-NMR (CDCl₃) δ: 1.60-1.80 (2H, m), 3.09-3.21 (1H, m), 3.37 (3H, s),3.36-3.60 (2H, m), 4.70-4.80 (1H, m), 5.12 (1H, s), 6.75-6.85 (2H, m),7.30-7.40 (1H, m), 8.30 (1H, s), 10.38 (1H, brs), 12.33 (1H, brs).

Example Y-5(5aR,6aS,10aR)-1-Hydroxy-2,12-dioxo-2,5,5a,7,8,9,10,10a,11,12-decahydro-6aH-6-oxa-4a,11a-diaza-naphthacene-3-carboxylicacid 2,4-difluoro-benzylamide [racemate]

1H-NMR (DMSO-d6) δ: 1.00-1.85 (9H, m), 2.90 (1H, t, J=4.2 Hz), 4.36 (1H,dd, J=4.2, 12.9 Hz), 4.44-4.57 (4H, m), 5.32 (1H, t, J=3.9 Hz),7.03-7.09 (1H, m), 7.20-7.27 (1H, m), 7.85-7.43 (1H, m), 8.49 (1H, s),10.34 (1H. brs).

Example Y-6(2S,9aR)-2-Ethyl-6-hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide Example Y-7(2R,9aS)-2-Ethyl-5-hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

1H-NMR (DMSO-d6) δ: 0.87 (3H, d, J=5.4 Hz), 1.40-1.51 (3H, m), 1.75 (1H,d, J=10.8 Hz), 3.22 (1H, t, J=10.2 Hz), 3.73-3.78 (1H, m), 4.41-4.57(4H, m), 5.29 (1H, s), 7.08-7.07 (1H, m), 7.21-7.26 (1H, m), 7.37-7.42(1H, m), 8.50 (1H, s), 10.34 (1H, brs), 12.48 (1H, s).

Example Y-10(2S,9aS)-5-Hydroxy-6,10-dioxo-2-phenyl-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

1H-NMR (CDCl3) δ: 1.70-1.82 (1H, m), 1.98 (1H, d, J=0.6 Hz), 3.40 (1H,t, J=9.6 Hz), m), 8.50 (1H, s), 10.38 (1H, s), 12.45 (1H, s).

Example Y-11(2S,9aS)-5-Hydroxy-2-isopropyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide Example Y-12(2R,9aR)-5-Hydroxy-2-isopropyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

1H-NMR (DMSO-d6) δ: 0.86 (6H, dd, J=4.8, 13.5 Hz), 1.41-1.49 (1H, m),1.57-1.69 (1H, m), 1.72-1.78 (1H, m), 3.20 (1H, t, J=8.4 Hz), 3.52-3.59(1H, m), 4.41-4.46 (5H, m), 5.29 (1H, s), 7.01-7.08 (1H, m), 7.21-7.26(1H, m), 7.37-7.43 (1H, m), 8.50 (1H, s), 10.35 (1H, brs), 12.48 (1H,s).

Example Y-13(3S,9aS)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diazo-anthracene-7-carboxylicacid 4-fluoro-benzylamide Example Y-14(3R,9aR)-5-Hydroxy-3-methyl-6,10-dioxo-8,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

1H-NMR (DMSO-d6) δ: 0.81 (3H, d, J=6.6 Hz), 1.84-1.93 (1H, m), 2.86 (1H,t, J=12.5 Hz), 3.48 (1H, t, J=11.1 Hz), 3.97-4.03 (1H, m), 4.41-4.60(3H, m), 4.52 (2H, d, J=5.9 Hz), J=5.9 Hz), 12.45 (1H, s).

Example Y-15(2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide Example Y-16(2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 2,4-difluoro-benzylamide

1H-NMR (DMSO-d6) δ: 1.14 (3H, d, J=6.0 Hz), 1.38 (1H, m), 1.75 (1H, d,J=13.8 Hz), 3.18-3.29 (1H, m), 3.95-4.06 (1H, m), 4.42-4.58 (3H, m),4.54 (2H, d, J=5.7 Hz), 5.30 (1H, t, J=3.9 Hz), 7.03-7.10 (1H, m),7.20-7.29 (1H, m), 7.35-7.44 (1H, m), 8.50 (1H, s), 10.35 (1H, t, J=5.7Hz), 12.48 (1H, s).

Example Y-17(2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide Example Y-18(2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylicacid 4-fluoro-benzylamide

1H-NMR (DMSO-d6) δ: 1.15 (3H, d, J=6.0 Hz), 1.35-1.50 (1H, m), 1.76 (1H,d, J=12.9 Hz), 3.23 (1H, td, J=13.0, 2.8 Hz), 3.95-4.03 (1H, m),4.41-4.59 (3H, m), 4.52 (2H, d, J=6.0 Hz), 5.30 (1H, t, J=3.9 Hz),7.12-7.19 (2H, m), 7.32-7.38 (2H, m), 8.52 (1H, s), 10.36 (1H, t, J=6.0Hz), 12.48 (1H, s).

Corresponding amino-alcohol derivatives used in syntheses of Y-1 to Y-18were prepared as optically pure version using methods similar to thosedescribed in the following reports.

-   3-Amino-2-methyl-propan-1-ol, and 4-Amino-butan-2-ol were prepared    according to the method of Russell A. Barrow (J. Am. Chem. Soc.    1995, 117, 2479-2490).-   3-Amino-butan-1-ol were prepared according to the method of P. Besse    (Tetrahedron Asymmetry 10(1999) 2213-2224).-   1-Amino-pentan-3-ol, 1-Amino-4-methyl-pentan-3-ol,    4-Amino-1-methoxy-butan-2-ol, and 3-Amino-1-phenyl-propan-1-ol were    prepared according to the method described in the following    literatures, U.S. Pat. Appl. Publ., 2004133029, 8 Jul. 2004, PCT    Int. Appl., 2002012173, 14 Feb. 2002.

All examples below consist of >95% ee and >6:1 diastereomeric purityunless indicated otherwise. The compounds shown in table ZZ consist ofmixtures of diastereomers at the depicted stereocenter in ratios of 1:1to >10:1. Stereocenters that were formed during the process' below havebeen assigned using NMR techniques well know in the art (1D and 2Dmethod) and/or using vibrational circular dichroism techniques.Stereochemical assignment determinations were performed onrepresentative examples and closely related compounds were assigned byanalogy in some cases. The schemes below are meant to be generalguidance to how examples were synthesized. It will be possible that oneskilled in the art may rearrange the order of steps or changesubstituents to apply the method described below and in the examples toconstruct compounds of the general formula. Additional methods known tothose skilled in the art or commonly present in the literature may alsobe applied to perform similar transformations and arriving at the samecompounds of the general formula or amino alcohol and diamineprecursors.

Example Z-1(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidesodium salt

a)(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-3-methyl-5,7dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.To a solution of 16a (409 mg, 0.87 mmol) in dichloroethane (20 mL) wasadded (2R)-2-amino-1-propanol (0.14 mL, 1.74 mmol) and 10 drops ofglacial acetic acid. The resultant solution was heated at reflux for 2h. Upon cooling, Celite was added to the mixture and the solventsremoved in vacuo and the material was purified via silica gelchromatography (2% CH₃OH/CH₂Cl₂ gradient elution) to give(3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(396 mg, 92%) as a glass. ¹H NMR (CDCl₃) δ 10.38 (m, 1H), 8.42 (s, 1H),7.54-7.53 (m, 2H), 7.37-7.24 (m, 4H), 6.83-6.76 (m, 2H), 5.40 (d, J=10.0Hz, 1H), 5.22 (d, J=10.0 Hz, 1H), 5.16 (dd, J=9.6, 6.0 Hz, 1H), 4.62 (m,2H), 4.41 (m, 1H), 4.33-4.30 (m, 2H), 3.84 (dd, J=12.0, 10.0 Hz, 1H),3.63 (dd, J=8.4, 7.2 Hz, 1H), 1.37 (d, J=6.0 Hz, 3H); ES⁺ MS: 496 (M+1).

b)(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidesodium salt. To a solution of(3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(396 mg, 0.80 mmol) in methanol (30 mL) was added 10% Pd/C (25 mg).Hydrogen was bubbled through the reaction mixture via a balloon for 2 h.The resultant mixture was filtered through Celite with methanol anddichloromethane. The filtrate was concentrated in vacuo to give(3R,11aS)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamideas a pink tinted white solid (278 mg, 86%). ¹H NMR (CDCl₃) δ 11.47 (m,1H), 10.29 (m, 1H), 8.32 (s, 1H), 7.36 (m, 1H), 6.82 (m, 2H), 5.31 (dd,J=0.6, 3.6 Hz, 1H), 4.65 (m, 2H), 4.47-4.38 (m, 3H), 3.93 (dd, J=12.0,10.0 Hz, 1H), 3.75 (m, 1H), 1.49 (d, J=5.6 Hz, 3H); ES⁺ MS: 406 (M+1).The above material (278 mg, 0.66 mmol) was taken up in ethanol (10 mL)and treated with 1 N sodium hydroxide (aq) (0.66 mL, 0.66 mmol). Theresulting suspension was stirred at room temperature for 30 min. Etherwas added and the liquids were collected to provide the sodium salt ofthe title compound as a white powder (291 mg, 99%). ¹H NMR (DMSO-d₆) δ10.68 (m, 1H), 7.90 (s, 1H), 7.85 (m, 1H), 7.20 (m, 1H), 7.01 (m, 1H),5.20 (m, 1H), 4.58 (m, 1H), 4.49 (m, 2H), 4.22 (m, 2H), 3.74 (dd,J=11.2, 10.4 Hz, 1H), 3.58 (m, 1H), 1.25 (d, J=4.4 Hz, 3H).

Example Z-2(4aR,13aS)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide

a)(4aR,13aS)—N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide.A solution of 16a (24 mg, 0.05 mmol), [(2S)-2-pyrrolidinylmethyl]amine(0.1 mL) and 2 drops of glacial acetic acid were heated under microwaveconditions at 140° C. for 10 min. Upon cooling, Celite was added to themixture and the solvents removed in vacuo and the material was purifiedvia silica gel chromatography (2% CH₃OH/CH₂Cl₂ gradient elution) to give(4aR,13aS)—N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(10 mg, 71%) as a white solid. ¹H NMR (CDCl₃) δ 10.41 (m, 1H), 8.38 (s,1H), 7.56 (m, 2H), 7.38-7.24 (m, 4H), 6.80 (m, 2H), 5.38 (d, J=9.6 Hz,1H), 5.10 (d, J=10.0 Hz, 1H), 4.62 (m, 2H), 4.40 (m, 1H), 4.25 (dd,J=12.0, 6.8 Hz, 1H), 4.10 (d, J=12.8 Hz, 1H), 3.83 (m, 1H), 3.71 (m,1H), 3.14-3.04 (m, 2H), 2.78 (m, 1H), 2.11-1.58 (m, 4H); ES⁺ MS: 521(M+1).

b)(4aR,13aS)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide.To a solution of(4aR,13aS)—N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(19 mg, 0.04 mmol) in methanol (8 mL) was added 10% Pd/C (10 mg).Hydrogen was bubbled through the reaction mixture via a balloon for 2 h.The resultant mixture was filtered through Celite with methanol anddichloromethane. The filtrate was concentrated in. vacuo to give thetitle compound (6 mg, 38%) as a white solid. ¹H NMR (CDCl₃) δ 11.73 (m,1H), 10.36 (m, 1H), 8.31 (s, 1H), 7.33 (m, 1H), 6.78 (m, 2H), 4.62 (m,2H), 4.50 (m, 1H), 4.27-4.19 (m, 2H), 3.87-3.77 (m, 2H), 3.16-3.08 (m,2H), 2.83 (m, 1H), 2.11-1.65 (m, 4H): ES⁺ MS: 431 (M+1).

Example Z-3(3aS,13aS)—N-[(2,4-Difluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide

a) N-BOC-(2S)-2-(Hydroxymethyl)-1-pyrrolidine. To a solution ofN-BOC-L-proline (4.17 g, 19.4 mmol) in THF (40 mL) at 0° C. was addedBH₃-THF (21.4 mL, 1 M in THF, 21.4 mmol) dropwise. The bath was removedand the resultant solution stirred at room temperature for 2 h. Methanolwas added to quench the mixture and the solvents were removed in vacuo.The residue was taken up in ethyl acetate and washed with sodiumbicarbonate and brine. The aqueous layers were extracted twice withethyl acetate. The combined organics wore dried over Na₂SO₄, filteredand concentrated to give N-BOC-(2S)-2-(hydroxymethyl)-1-pyrrolidine(3.82 g, 98%) as a clear oil. This material was used without furtherpurification. ¹H NMR (CDCl₃) δ 3.94 (m, 1H), 3.62 (dd, J=11.2, 3.2 Hz,1H), 3.56 (dd, J=10.8, 7.2 Hz, 1H), 3.44 (m, 1H), 3.29 (m, 1H), 2.62(br, 1H), 1.98 (m, 1H), 1.85-1.72 (m, 2H), 1.58 (m, 1H).

b) N-BOC-(2S)-2-({[(4-Methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidine.To a cold (0° C.) solution of N-BOC-(2S)-2-(hydroxymethyl)-1-pyrrolidine(350 mg, 1.74 mmol) in dichloromethane (20 mL) was added triethylamine(0.29 mL, 2.08 mmol), and toluenesulfonyl chloride (398 mg, 2.08 mmol).N,N-demethylaminopyridine (70 mg) was added and the resultant solutionwas allowed to warm to rt as the bath warmed and stirred for 4 h. Waterwas added and the layers separated. The aqueous layer was washed withsodium bicarbonate and then with brine. The combined organics were driedover Na₂SO₄, filtered and concentrated followed by flash chromatographypurification to give—N-BOC-(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidine (460mg, 75%) as a clear oil. ¹H NMR exists as rotomers (CDCl₃) δ 7.77 (d,2H), 7.33 (m, 2H), 4.08 (m, 1H), 3.07-3.88 (m, 1H), 3.35-3.25 (m, 2H),2.43 (s, 3H), 1.95-1.79 (m, 4H), 1.40 and 1.35 (s, 9H rotomeric BOCt-butyl).

c) N-BOC-(2S)-2-Cyano-1-pyrrolidino. A mixture of—N-BOC-(2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-pyrrolidine (460mg, 1.29 mmol) and KCN (256 mg, 3.88 mmol) were heated at 90° C. in DMSO(10 mL) for 6.65 h. The mixture was cooled to room temperature and EtOAcand water were added. The organics were washed with water twice and thenwith brine. The aqueous layers were extracted with EtOAc and thecombined organics dried over Na₂SO₄, filtered and concentrated followedby flash chromatography purification to giveN-BOC-(2S)-2-cyano-1-pyrrolidine (179 mg, 66%) as an oil. ¹H NMR existsas rotomers (CDCl₃) δ 3.99 (m, 1H), 3.43-3.37 (m, 2H), 2.83-2.51 (m,2H), 2.17-1.83 (m, 4H), 1.46 and 1.44 (s, 9H rotomeric BOC t-butyl).

d) N-BOC-(2S)-2-(2-Aminoethyl)-1-pyrrolidine. A solution ofN-BOC-(2S)-2-cyano-1-pyrrolidine (170 mg, 0.85 mmol) in ethanolsaturated with anhydrous ammonia was treated with Raney-Ni (1 mL of 50%aq. Suspension) and 50 psi of H₂ overnight. The mixture was filteredthrough Celite and the filtrate was concentrated in vacuo. The residuewas purified by flash chromatography (10% CH₃OH/CH₂Cl₂ with 1% NH₄OHgradient elution) through a short plug of silica gel to give—N-BOC-(2S)-2-(2-aminoethyl)-1-pyrrolidine (90 mg, 50%) as a clear oil.¹H NMR exists as rotomers (CDCl₃) δ 3.88-3.77 (m, 1H), 3.33-3.24 (m,2H), 2.66 (m, 2H), 1.89-1.54 (m, 6H), 1.40 (s, 9H).

e) {2-[(2S)-2-Pyrrolidinyl]ethyl}amine. A solution of—N-BOC-(2S)-2-(2-aminoethyl)-1-pyrrolidine (90 mg, 0.42 mmol) in THF (6mL) was treated with 4 N HCl (aq) (2 mL) and stirred at room temperaturefor 3 h. The mixture was concentrated in vacuo to give the titlecompound as its HCl salt. A portion of this material (40 mg) wasdissolved in methanol and treated with solid supported carbonate resin(MP-Carbonate, Argonaut Technologies) to freebase the amines. After 30minutes, the solution was filtered through a fritted tube and thesolvents removed carefully in vacuo to give{2-[(2S)-2pyrrolidinyl]ethyl}amine (30 mg) as its free base. ¹H NMR(CDCl₃) δ 3.06 (m, 1H), 2.94 (m, 1H), 2.88 (m, 1H), 2.79-2.69 (m, 2H),1.90-1.56 (m, 6H).

f)(3aS,13aS)—N-[(2,4-Difluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide.A solution of 16a (30 mg, 0.06 mmol),{2-[(2S)-2-pyrrolidinyl]ethyl}amine (30 mg, 0.26 mmol) and 2 drops ofglacial acetic acid were heated under microwave conditions at 140° C.for 10 min. Upon cooling, Celite was added to the mixture and thesolvents removed in vacuo and the material was purified via silica gelchromatography (2% CH₃OH/CH₂Cl₂ gradient elution) to give(3aS,13aS)—N-[(2,4-Difluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide.(25 mg, 74%) as a film. ¹H NMR (CDCl₃) δ 10.44 (m, 1H), 8.32 (s, 1H),7.59 (m, 2H), 7.38-7.24 (m, 4H), 6.80 (m, 2H), 5.28-5.22 (m, 2H), 4.67(dd, J=13.6, 2.8 Hz, 1H), 4.62 (m, 2H), 4.26 (m, 1H), 4.11-4.03 (m, 2H),2.91 (m, 1H), 2.81 (m, 1H), 2.37 (m, 1H), 2.24 (m, 1H), 1.92 (m, 1H),1.82-1.76 (m, 3H), 1.52-1.38 (m, 2H); ES⁺ MS: 535 (M+1).

g)(3aS,13aS)—N-[(2,4-Difluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide.To a solution of(3aS,13aS)—N-[(2,4-difluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide(25 mg, 0.05 mmol) in methanol (8 mL) was added 10% Pd/C (10 mg).Hydrogen was bubbled through the reaction mixture via a balloon for 18h. The resultant mixture was filtered through Celite with methanol anddichloromethane. The filtrate was concentrated in vacuo to give thetitle compound (14 mg, 67%) as a white solid. ¹H NMR (CDCl₃) δ 12.53(br, 1H), 10.44 (s, 1H), 8.20 (s, 1H), 7.34 (m, 1H), 6.78 (m, 2H),4.71-4.58 (m, 3H), 4.29-4.14 (m, 3H), 2.99 (m, 1H), 2.88 (m, 1H), 2.44(m, 1H), 2.30 (m, 1H), 1.97-1.38 (m, 6H); ES⁺ MS: 445 (M+1).

Example Z-4(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamidesodium salt

a) [(2R)-2-Pyrrolidinylmethyl]amine. To a solution ofN-BOC-(2R)-2-(aminomethyl)-1-pyrrolidine (1.37 g, 6.85 mmol) in THF (20mL) was added 4 NHC (aq) (8 mL). The resultant solution was stirred atroom temperature overnight. The solvents were removed in vacuo and theresidue was treated with MP-carbonate resin in methanol anddichloromethane. After 1 h, the rosin was removed via filtration througha fritted tube and the volatiles were removed carefully in vacuo toproduce the free based amine (760 mg crude >100%) as a oil. Thismaterial was used without further purification. ¹H NMR (CDCl₃) δ 3.13(m, 1H), 2.02 (m, 1H), 2.82-2.62 (m, 5H), 1.88-1.80 (m, 4H).

b)(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide.In a similar manner as described in example Z-2 from 16a (435 mg, 0.98mmol) and [(2R)-2-pyrrolidinylmethyl]amine (200 mg, 2.0 mmol) in1,2-dichloroethane (20 mL) and 15 drops of glacial acetic acid wasobtained(4aS,13aR)—N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(321 mg, 67%) as a white solid. ¹H NMR (CDCl₃) δ 10.41 (m, 1H), 8.35 (s,1H), 7.56 (m, 2H), 7.55-7.24 (m, 4H), 6.80 (m, 2H), 5.35 (d, J=10.0 Hz,1H), 5.13 (d, J=10.0 Hz, 1H), 4.60 (m, 2H), 4.38 (dd, J=10.4, 3.2 Hz,1H), 4.21 (dd, J=12.0, 6.8 Hz, 1H), 4.04 (dd, J=12.4, 2.8 Hz, 1H), 3.77(apparent t, J=11.6 Hz, 1H), 3.68 (m, 1H), 3.11-3.00 (m, 2H), 2.75 (m,1H), 2.08-1.84 (m, 3H), 1.65 (m, 1H); ES⁺ MS: 521 (M+1).

c)(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide.In a similar manner as described in example Z-2 from(4aS,13aR)—N-[(2,4-difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(518 mg, 0.99 mmol) and 10% Pd/C (35 mg) in methanol (40 mL) wasobtained(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(430 mg, 99%) as a white solid. ¹H NMR (CDCl₃) δ 11.73 (m, 1H), 10.36(m, 1H), 8.32 (s, 1H), 7.35 (m, 1H), 6.79 (m, 2H), 4.64 (m, 2H), 4.54(dd, J=10.8, 4.0 Hz, 1H), 4.28-4.19 (m, 2H), 3.90-3.79 (m, 2H),3.18-3.10 (m, 2H), 2.84 (m, 1H), 2.14-1.92 (m, 3H), 1.72 (m, 1H).

d) (4aS,13aR-N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamidesodium salt. In a similar manner as described in example Z-1 from(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(430 mg, 1.0 mmol) and sodium hydroxide (1.0 mL, 1.0 M aq, 1.0 mmol) in20 mL of ethanol was formed the corresponding sodium salt (425 mg, 94%)as a white solid. ¹H NMR (D₂O) δ 7.85 (s, 1H), 7.23 (m, 1H), 6.82 (m,2H), 4.51-4.46 (m, 3H), 4.28 (m, 1H), 3.95 (m, 1H), 3.84 (m, 1H), 3.62(m, 1H), 3.16 (m, 1H), 2.89 (m, 1H), 2.84 (m, 1H), 1.90 (m, 2H), 1.73(m, 1H), 1.60 (m, 1H). ES⁺ MS: 431 (M+1).

Example Z-5(4aS,13aR)—N-[(4-Fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16 (60 mg, 0.13 mmol) and[(2R)-2-pyrrolidinylmethyl]amine (100 mg, 1.0 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(4aS,13aR)—N-[(4-fluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(60 mg, 91%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(4aS,13aR)—N-[(4-fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(21 mg, 42%) as a white solid. ¹H NMR (CDCl₃) δ 11.72 (m, 1H), 1.37 (m,1H), 8.33 (s, 1H), 7.29 (m, 2H), 6.97 (m, 2H), 4.57 (m, 2H), 4.52 (m,1H), 4.24-4.19 (m, 2H), 3.87-3.76 (m, 2H), 3.14-3.07 (m, 2H), 2.82 (m,1H), 2.11-1.89 (m, 3H), 1.68 (m, 1H); ES⁺ MS: 413 (M+1).

Example Z-6(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (37 mg, 0.08 mmol) and(2S)-2-amino-3-phenyl-1-propanol (35 mg, 0.24 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-3-(phenylmethyl)-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(41 mg, 91%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.(25 mg, 75%) as a white solid. ¹H NMR (CDCl₃) δ 11.47 (br, 1H), 10.28(m, 1H), 8.35 (m, 1H), 7.37-7.26 (m, 4H), 7.18 (m, 2H), 6.79 (m, 2H),5.03 (m, 1H), 4.64-4.61 (m, 3H), 4.40 (m, 1H), 4.23 (apparent t, J=7.2Hz, 1H), 3.96 (dd, J=8.8, 6.4 Hz, 1H), 3.88 (apparent t, J=11.2 Hz, 1H),3.37 (dd, J=13.6, 3.2 Hz, 1H), 2.99 (dd, J=13.2 8.8 Hz, 1H); ES⁺ MS: 482(M+1).

Example Z-7(3aS,13aS)—N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16 (84 mg, 0.13 mmol) and{2-[(2S)-2-Pyrrolidinyl]ethyl}amine (150 mg, 1.3 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(3aS,13aS)—N-[(4-fluorophenyl)methyl]-7,9-dioxo-8-[(phenylmethyl)oxy]-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide(86 mg, 90%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3aS,13aS)—N-[(4-Fluorophenyl)methyl]-8-hydroxy-7,9-dioxo-1,2,3,3a,4,5,7,9,13,13a-decahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrrolo[1,2-c]pyrimidine-10-carboxamide.(63 mg, 88%) as a white solid. ¹H NMR (CDCl₃/CD₃OD) δ 10.45 (m, 1H),8.23 (e, 1H), 7.35 (m, 2H), 6.94 (t, J=8.8 Hz, 2H), 4.63 (m, 1H),4.58-4.48 (m, 2H), 4.33 (dd, J=13.6, 3.6 Hz, 1H), 4.21 (m, 1H), 4.11 (m,1H), 2.98 (m, 1H), 2.85 (td, J=13.2, 3.2 Hz, 1H), 2.41 (m, 1H), 2.29 (m,1H), 1.92 (m, 1H), 1.83-1.75 (m, 3H), 1.54-1.35 (m, 2H); ES⁺ MS: 427(M+1).

Example Z-8(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1S)-1-methylpropyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidesodium salt

The title compound was made in two steps using a similar process to thatdescribed in example Z-1. 16a (417 mg, 0.89 mmol) and L-isoleucinol (259mg, 2.21 mmol) were reacted in 1,2-dichloroethane (40 mL) with aceticacid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-[(1S)-1-methylpropyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(426 mg, 90%). This material was hydrogenated in a second step asdescribed in example Z-1 to give(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(1S)-1-methylpropyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(376 mg, 99%) as a coarse white solid. 2H NMR (CDCl₃) δ 11.43 (br, 1H),10.27 (br, 1H), 8.32 (s, 1H), 7.33 (m, 1H), 6.79 (m, 2H), 5.26 (dd,J=9.6, 4.0 Hz, 1H), 4.62 (m, 2H), 4.42-4.35 (m, 2H), 4.19 (dd, J=8.8,7.2 Hz, 1H), 4.01 (dd, J=8.8, 5.6 Hz, 1H), 3.86 (dd, J=12.0, 10.0 Hz,1H), 2.27 (m, 1H), 1.40 (m, 1H), 1.15 (m, 1H), 0.97 (t, J=7.2 hz, 3H),0.91 (d, J=6.8 Hz, 3H); ES⁺ MS: 448 (M+1). This material (360 mg, 0.81mmol) was treated with sodium hydroxide (0.81 mL, 1.0 M, 0.81 mmol) inethanol (15 mL) as described in example Z-1 to provide its correspondingsodium salt (384 mg, 99%) as a white solid. ¹H NMR (DMSO-d₆) δ 10.82 (m,1H), 7.80 (m, 1H), 7.33 (m, 1H), 7.18 (m, 1H), 7.00 (m, 1H), 5.14 (m,1H), 4.47 (d, J=5.6 Hz, 2H), 4.31 (m, 1H), 4.18 (m, 1H), 3.96 (m, 1H),3.84 (m, 1H), 3.71 (m, 1H), 3.40 (m, 1H), 1.88 (m, 1H), 1.36 (m, 1H),1.04 (m, 1H), 0.85 (t, J=7.2 Hz, 3H), 0.80 (d, J=6.8 Hz, 3H); ES⁺ MS:448 (M+1).

Example Z-9(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamidesodium salt

The title compound was made in two steps using a similar process to thatdescribed in example Z-1. 16a (510 mg, 1.08 mmol) and(2S)-2-amino-1-propanol (0.17 mL, 2.17 mmol) were reacted in1,2-dichloroethane (20 mL) with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(500 mg, 93%). This material was hydrogenated in a second step asdescribed in example Z-1 to give3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(386 mg, 94%) as a tinted white solid. ¹H NMR (CDCl₃) δ 11.46 (m, 1H),10.28 (m, 1H), 8.32 (s, 1H), 7.35 (m, 1H), 6.80 (m, 2H), 5.30 (dd,J=10.0, 4.0 Hz, 1H), 4.63 (m, 2H), 4.48-4.37 (m, 3H), 3.91 (dd, J=12.0,10.0 Hz, 1H), 3.73 (m, 1H), 1.48 (d, J=6.0 Hz, 3H); ES⁺ MS: 406 (M+1).This material (385 mg, 0.95 mmol) was treated with sodium hydroxide(0.95 mL, 1.0 M, 0.95 mmol) in ethanol (15 mL) as described in exampleZ-1 to provide its corresponding sodium salt (381 mg, 94%) as a whitesolid. ¹H NMR (DMSO-d) δ 10.66 (m, 1H), 7.93 (s, 1H), 7.33 (m, 1H), 7.20(m, 1H), 7.01 (m, 1H), 5.19 (m, 1H), 4.50 (m, 1H), 4.48 (m, 2H), 4.22(m, 2H), 3.75 (m, 1H), 3.57 (m, 1H), 1.24 (d, J=5.6 Hz, 3H).

Example Z-10(3S,11aR)—N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16 (100 mg, 0.22 mmol) and(2S)-2-amino-1-propanol (0.10 mL, 1.28 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(3S,11aR)—N-[(4-fluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(100 mg, 95%). This material was hydroginated in a second step asdescribed in example Z-2 to give(3S,11aR)—N-[(4-Fluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(80 m g, 99%) as a white solid. ¹H NMR (CDCl₃) δ 11.43 (br, 1H), 10.28(br, 1H), 8.35 (s, 1H), 7.28 (m, 2H), 6.97 (m, 2H), 5.29 (m, 1H),4.55-4.38 (m, 5H), 3.89 (apparent t, J=10.8 Hz, 1H), 3.70 (m, 1H), 1.45(d, J=5.6 Hz, 3H); ES⁺ MS: 386 (M−1).

Example Z-11(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (41 mg, 0.09 mmol) and freebasedL-tert-leucinol (59 mg, 0.50 mmol) were reacted in dichloromethane (2mL) with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-(1,1-dimethylethyl)-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(40 mg, 86%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-(1,1-dimethylethyl)-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(33 mg, 99%) as a tinted white solid. ¹H NMR (CDCl₃) δ 10.29 (s, 1H),8.37 (s, 1H), 7.34 (m, 1H), 6.79 (m, 2H), 5.43 (m, 1H), 4.62 (m, 2H),4.36 (m, 2H), 4.21 (m, 1H), 3.99 (, 1H), 3.81 (m, 1H), 1.03 (s, 9H); ES⁺MS: 448 (M+1).

Example Z-12(3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16 (41 mg, 0.09 mmol) and freebasedL-tert-leucinol (59 mg, 0.50 mmol) were reacted in dichloromethane (2mL) with acetic acid to give(3S,11aR)-3-(1,1-dimethylethyl)-N-[(4-fluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(40 rag, 85%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(32 mg, 97%) as a tinted white solid. ¹H NMR (CDCl₃) δ 11.15 (br, 1H),10.32 (s, 1H), 8.38 (s, 1H), 7.29 (m, 2H), 6.98 (m, 2H), 5.43 (m, 1H),4.58 (m, 2H), 4.36 (m, 2H), 4.21 (m, 1H), 3.99 (, 1H), 3.79 (m, 1H),1.02 (s, 9H); ES⁺ MS: 430 (M+1).

Example Z-13(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (33 mg, 0.07 mmol) and L-phenylglycinol(19 mg, 0.14 mmol) were reacted in dichloromethane (2 mL) with aceticacid to give(3S,11aR)—N-[(4-fluorophenyl)methyl]-5,7dioxo-3-phenyl-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(37 mg, 95%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(33 mg, 99%) as a tinted white solid. ¹H NMR (CDCl₃) δ 11.23 (br, 1H),10.27 (s, 1H), 8.39 (s, 1H), 7.43-7.32 (m, 6H), 6.80 (m, 2H), 5.58 (d,J=6.8 Hz, 1H), 5.37 (apparent t, J=6.8 Hz, 1H), 4.67-4.62 (m, 3H), 4.54(d, J=10.4 Hz, 1H), 4.11 (m, 1H), 4.01 (m, 1H); ES⁺ MS: 468 (M+1).

Example Z-14(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(hydroxymethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (50 mg, 0.10 mmol) and(2R)-2-amino-3-[(phenylmethyl)oxy]-1-propanol (0.1 mL) were reacted indichloromethane (2 mL) with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-3-{[(phenylmethyl)oxy]methyl}-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(61 mg, 99%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(hydroxymethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(37 mg, 87%) as a tinted white solid. ¹H NMR (CDCl₃/CD₃OD) δ 8.23 (s,1H), 7.32 (m, 1H), 6.79 (m, 2H), 5.31 (d, J=7.6 Hz, 1H), 4.56 (s, 2H),4.42-4.36 (m, 3H), 4.17-4.11 (m, 2H), 3.85 (m, 1H), 3.62 (d, J=11.2 Hz,1H).

Example Z-15(2S,3R)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (25 mg, 0.05 mmol) and(1S,2R)-(+)-norephedrine (0.1 mL) were reacted in dichloromethane (2 mL)with acetic acid to give(2S,3R)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-2-phenyl-6-[(phenylmethyl)oxy]-2,3,6,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(30 mg, 99%). This material was hydrogenated in a second stop asdescribed in example Z-2 to give(2S,3R)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(25 mg, 91%) as a white solid. This material is a single diastereomer(>6:1 diastereomeric ratio but unconfirmed relative stereochemistry atthe aminal center). ¹H NMR (CDCl₃/CD₃OD) δ 10.28 (m, 1H), 8.38 (s, 1H),7.10-7.30 (m, 6H), 6.78 (m, 2H), 5.70 (d, J=7.6 Hz, 1H), 5.36 (d, J=5.2Hz, 1H), 4.82 (m, 1H), 4.61 (m, 2H), 4.47 (d, J=10.4 Hz, 1H), 4.00(apparent t, J=10.4 Hz, 1H), 0.94 (d, J=6.4 Hz, 3H); ES⁺ MS: 482 (M+1).

Example Z-16(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (34 mg, 0.07 mmol) and(2R)-2-amino-3-phenyl-1-propanol (D-phenylalaninol) (50 mg, 0.33 mmol)were reacted in dichloromethane (2 mL) with acetic acid to give(3R,11aS)—N-[(2,4-difluorophenyl)methyl]-5,7dioxo-3-(phenylmethyl)-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(29 mg, 70%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-3-(phenylmethyl)-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(24 mg, 98%) as a white solid. ¹H NMR (CDCl₃) δ 11.46 (br, 1H), 10.27(m, 1H), 8.33 (m, 1H), 7.32-7.16 (m, 6H), 6.78 (m, 2H), 5.02 (m, 1H),4.61 (m, 3H), 4.30 (m, 1H), 4.22 (m, 1H), 3.95 (m, 1H), 3.87 (m, 1H),3.36 (m, 1H), 2.97 (dd, J=13.2 8.8 Hz, 1H); ES⁺ MS: 482 (M+1).

Example Z-17(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(2-methylpropyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (32 mg, 0.07 mmol) and(2R)-2-amino-4-methyl-1-pentanol (0.1 mL) were reacted indichloromethane (2 mL) with acetic acid to give(3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-(2-methylpropyl)-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(43 mg, 99%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(2-methylpropyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(32 mg, 90%) as a white solid. ¹H NMR (CDCl₃) δ 11.47 (br, 1H), 10.20(m, 1H), 8.35 (s, 1H), 7.39 (m, 1H), 6.80 (m, 2H), 5.31 (m, 1H), 4.62(m, 2H), 4.44 (m, 2H), 4.37 (m, 1H), 3.88 (m, 1H), 3.84 (dd, J=8.0, 5.6Hz, 1H), 2.04 (m, 1H), 1.62 (m, 1H), 1.41 (m, 1H), 1.00 (d, J=5.6 Hz,3H), 0.09 (d, J=6.0 Hz, 3H); ES⁺ MS: 448 (M+1).

Example Z-18(5aR,14aR)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide

a) 1,1-Dimethylethyl (2R)-2-(aminocarbonyl)-1-piperidinecarboxylate. Toa cold (0° C.) solution of(2R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-piperidinecarboxylic acid(1.0 g, 4.36 mmol) in THF (20 mL) was added triethylamine (0.60 mL, 4.36mmol) followed by slow addition of methyl chloroformate (0.34 mL, 4.36mmol). After a few minutes a suspension had formed. To this mixture wasadded concentrated NH₄OH (1.5 mL) and the solution was allowed to warmto rt as the bath warmed and stirred for a total of 4 h. The mixture wasconcentrated in vacuo and the residue was taken up in EtOAc. The organiclayer was washed with citric acid, bicard and then brine, dried overNa₂SO₄. Filtration and concentration gave 1,1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate (1.0 g, 99%). ¹H NMR(CDCl₃) δ 6.03 (br, 1H), 5.45 (br, 1H), 4.77 (br, 1H), 4.06 (br, 1H),2.82 (m, 1H), 2.29 (m, 1H), 1.67-1.43 (m, 13H).

b) 1,1-Dimethylethyl (2R)-2-cyano-1-piperidinecarboxylate. To a cold (0°C.) solution of 1,1-dimethylethyl(2R)-2-(aminocarbonyl)-1-piperidinecarboxylate (260 mg, 1.17 mmol) inTHF (10 mL) was added triethylamine (0.33 mL, 2.34 mmol) and thentrifluoroacetic anhydride (0.17 mL, 1.17 mmol). The mixture was stirredat 0° C. for 1 h and concentrated in vacuo. The residue was taken up inEtOAc and washed successively with sodium bicarbonate, 0.5 N HCl andbrine. The organics were dried over Na₂SO₄, filtered and concentrated togive 1,1-dimethylethyl (2R)-2-cyano-1-piperidinecarboxylate (255 mg,99%) as a crystalline solid upon standing. ¹H NMR (CDCl₃) δ 5.23 (br,1H), 4.05 (br, 1H), 2.93 (br, 1H), 1.93-1.39 (m, 6H), 1.46 (s, 9H).

c) 1,1-Dimethylethyl (2R)-2-(aminomethyl)-1-piperidinecarboxylate. Anammonia saturated ethanol solution of 1,1-dimethylethyl(2R)-2-cyano-1-piperidinecarboxylate (255 mg, 1.19 mmol) was reducedwith Raney-Ni in a similar manner to that described in example Z-3 togive after filtration through a short plug of silica, 1,1dimethylethyl(2R)-2-(aminomethyl)-1-piperidinecarboxylate (236 mg, 91%), as an oil.¹H NMR (CDCl₃/CD₃OD) δ 4.15 (br, 1H), 3.97 (m, 1h), 2.96 (m, 1H),2.75-2.69 (m, 2H), 2.23-2.08 (m, 3H), 1.59-1.55 (m, 3H), 1.43 (s, 9H).

d) [(2R)-2-Piperidinylmethyl]amine bis HCl salt. A solution of1,1-dimethylethyl (2R)-2-(aminomethyl)-1-piperidinecarboxylate (236 mg,1.08 mmol) in THF (10 mL) was treated with 4 N HCl (3 mL) as describedin example Z-3 to give the bis HCl salt of[(2R)-2-Piperidinylmethyl]amine. ¹H NMR (DMSO-d₆) δ 0.67 (br, 1H), 9.48(br, 1H), 8.48 (br, 2H), 3.70 (br, 2H), 3.20 (m, 1H), 3.04 (m, 1H), 2.86(m, 1H), 1.89-1.41 (m, 6H).

e)(5aR,14aR)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (50 mg, 0.11 mmol) and[(2R)-2-Piperidinylmethyl]amine (150 mg, 1.31 mmol) (free based usingcarbonate resin as described in example Z-3) were reacted indichloromethane (2 mL) with acetic acid to give(5aR,14aR)—N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)oxy]-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide(50 mg, 88%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(5aR,14aR)—N-[(2,4-difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide(11 mg, 44%) as a white solid, ¹H NMR (CD₃OD/CDCl₃) δ 10.46 (m, 1H),8.32 (a, 1H), 7.31 (m, 1H), 6.80 (m, 2H), 4.64-4.52 (m, 3H), 4.14 (dd,J=10.4, 2.8 Hz, 1H), 3.91-8.82 (m, 2H), 3.19 (apparent t, J=10.8 Hz,1H), 3.08 (d, J=10.4 Hz, 1H), 2.50 (m, 1H), 2.27 (m, 1H), 1.99-1.30 m,6H); ES⁺ MS: 445 (M+1).

Example Z-19(2S,3S)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(methyloxy)methyl]-5,7-dioxo-2-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (36 mg, 0.07 mmol) and(2R)-2-amino-4-methyl-1-pentanol (0.1 mL) were reacted indichloromethane (2 mL) with acetic acid to give(2S,3S)—N-[(2,4-difluorophenyl)methyl]-3-[(methyloxy)methyl]-5,7-dioxo-2-phenyl-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide.This material was hydrogenated in a second step as described in exampleZ-2 to give(2S,3S)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(methyloxy)methyl]-5,7-dioxo-2-phenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(25 mg, 64% for 2 stops) as a white solid. This material is a singlediastereomer (>6:1 diastereomeric ratio but unconfirmed relativestereochemistry at the aminal center). ¹H NMR (CDCl₃) δ 11.48 (br, 1H),10.30 (m, 1H), 8.39 (s, 1H), 7.39-7.24 (m, 6H), 6.78 (m, 2H), 5.46 (dd,J=10.0, 8.6 Hz, 1H), 5.33 (d, J=7.2 Hz, 1H), 4.63 (m, 2H), 4.54 (dd,J=12.4, 4.0 Hz, 1H), 4.19 (m, 1H), 4.12 (dd, J=10.4, 8.2 Hz, 1H), 4.06(m, 1H), 3.55 (dd, J=10.4, 1.6 Hz, 1H), 3.40 (s, 3H); ES⁺ MS: 512 (M+1).

Example Z-20(3S,11aR)-3-(Cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (36 mg, 0.08 mmol) and(2S)-2-amino-3-cyclohexyl-1-propanol (30 mg, 0.19 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(3S,11aR)-3-(cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-n]pyrido[1,2-d]pyrazine-8-carboxamide(27 mg, 61%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3S,11aR)-3-(cyclohexylmethyl)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(25 mg, 99%) as a white solid. ¹H NMR (CDCl₃) δ 11.48 (br, 1H), 10.28(s, 1H), 8.33 (s, 1H), 7.33 (m, 1H), 6.78 (m, 2H), 5.29 (m, 1H), 4.61(m, 2H), 4.47-4.33 (m, 3H), 3.87-3.81 (m, 2H), 2.05 (m, 1H), 1.75-1.64(m, 6H), 1.39 (m, 1H), 1.25-1.14 (m, 3H), 1.02-0.97 (m, 2H); ES⁺ MS: 488(M+1).

Example Z-21(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-1. 16a (42 mg, 0.09 mmol) and(2S)-2-amino-3-methyl-1-butanol (0.1 mL) were reacted in1,2-dichloroethane (8 mL) with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-(1-methylethyl)-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(40 mg, 86%). This material was hydrogenated in a second step asdescribed in example Z-1 to give(3S,11aR)—N-[(2,4-difluorophenyl)ethyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(34 mg, 90%) as a white solid. ¹H NMR (CDCl₃) δ 10.29 (br, 1H), 8.36 (s,1H), 7.33 (m, 1H), 6.79 (m, 2H), 5.29 (d, J=6.4 Hz, 1H), 4.61 (m, 2H),4.44 (d, J=9.6 Hz, 1H), 4.34 (m, 1H), 4.17 (m, 1H), 4.02 (dd, J=8.4, 5.2Hz, 1H), 3.86 (m, 1H), 2.37 (m, 1H), 0.97 (m, 6H); ES⁺ MS: 434 (M+1).

Example Z-22(5aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-5a,6a,7,11,13,14a-hexahydro-5H-indeno[1′,2′:4,5][1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-10-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-1. 16a (42 ing, 0.09 mmol) and(1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol (100 mg, 0.67 mmol) werereacted in 1,2-dichloroethane (5 mL) with acetic acid to give(5aR,14aS)—N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-5a,6a,7,11,13,14a-hexahydro-5H-indeno[1′,2′:4,5][1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-10-carboxamide(55 mg, 99%). This material was hydrogenated in a second step asdescribed in example Z-1 to give(5aR,14aS)—N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-5a,6a,7,11,13,14a-hexahydro-5H-indeno[1′,2′:4,5][1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine10-carboxamide (45 mg, 97%) as a white solid. ¹H NMR (CDCl₃) δ 10.28 (m,1H), 8.33 (s, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.34-7.19 (m, 4H), 6.78 (m,2H), 5.96 (d, J=6.0 Hz, 1H), 5.32 (m, 1H), 5.22 (m, 1H), 4.60 (m, 2H),4.45 (d, J=9.2 Hz, 1H), 3.96 (apparent t, J=10.8 Hz, 1H), 3.40 (dd,J=18.0, 6.8 Hz, 1H), 3.24 (d, J=17.6 Hz, 1H); ES⁺ MS: 480 (M+1).

Example Z-23 & Z-24(2S,3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7dioxo-2,3-diphenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide&(2S,3R,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compounds were made in two steps using a similar process tothat described in example Z-1. 16a (40 mg, 0.09 mmol) and(1S,2R)-2-amino-1,2-diphenylethanol (50 mg, 0.23 mmol) were reacted in1,2-dichloroethane (5 mL) with acetic acid to give(2S,3R,11aS)—N-[(2,4-difluorophenyl)methyl]-5,7-dioxo-2,3-diphenyl-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(34 mg, 63%) and(2S,3R,11aR)—N-[(2,4-difluorophenyl)methyl]5,7-dioxo-2,3-diphenyl-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(13 mg, 24%). These materials were hydrogenated in a second step asdescribed in example Z-1 to give(2S,3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(example Z-23, 20 mg, 99%) as a white solid and(2S,3R,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3-diphenyl-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(example Z-24, 10 mg, 89%) as a white solid respectively. For exampleZ-23: ¹H NMR (DMSO-d₆) δ 10.20 (t, J=5.6 Hz, 1H), 8.55 (s, 1H), 7.38 (m,1H), 7.22 (m, 1H), 7.11-6.95 (m, 11H), 6.16 (dd, J=10.4, 3.6 Hz, 1H),5.71 (m, 2H), 4.90 (m, 1H), 4.54 (m, 2H), 4.38 (t, J=11.2 Hz, 1H); ES⁺MS: 544 (M+1). For example Z-24: ¹H NMR (CDCl₃) δ 11.64 (br, 1H), 10.30(s, 1H), 8.45 (s, 1H), 7.34 (m, 1H), 7.01-6.00 (m, 10H), 6.80 (m, 2H),5.56 (m, 2H), 5.42 (d, J=6.4 Hz, 1H), 4.73 (m, 1H), 4.63 (m, 2H), 4.49(m, 1H); ES⁺ MS: 544 (M+1).

Example Z-25(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-1. 16a (40 mg, 9.90 mmol) and(2R)-2-amino-3-methyl-1-butanol (0.1 mL) were reacted in1,2-dichloroethane (8 mL) with acetic acid to give(3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-(1-methylethyl)-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(41 mg, 92%). This material was hydrogenated in a second step asdescribed in example Z-1 to give(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1-methylethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(32 mg, 94%) as a white solid. ¹H NMR (CDCl₃) δ 11.42 (br, 1H), 10.27(br, 1H), 8.34 (s, 1H), 7.31 (m, 1H), 6.78 (m, 2H), 5.28 (d, J=6.0 Hz,1H), 4.60 (m, 2H), 4.42 (m, 1H), 4.33 (m, 1H), 4.16 (m, 1H), 4.01 (dd,J=8.8, 5.2 Hz, 1H), 3.85 (m, 1H), 2.37 (m, 1H), 0.97 (d, J=6.8 Hz, 3H),0.95 (d, J=6.4 Hz, 3H); ES⁺ MS: 434 (M+1).

Example Z-26(3R,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-1. 16a (48 mg, 9.90 mmol) and(2S)-2-amino-4-(methylthio)-1-butanol (0.1 mL) were reacted in1,2-dichloroethane (5 mL) with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-[2-(methylthio)ethyl]-5,7-dioxo-6[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(41 mg, 81%). This material (20 mg, 0.04 mmol) was treated withtrifluoroacetic acid (1 mL) in dichloromethane (3 mL) at 0° C. to rtover 6 h. The mixture was concentrated in vacuo and subjected to reversephase preparative HPLC purification to provide(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylthio)ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(12 mg, 72%) as a white solid. ¹H NMR (CDCl₃) δ 11.35 (br, 1H), 10.25(s, 1H), 8.34 (s, 1H), 7.33 (m, 1H), 6.70 (m, 2H), 5.32 (m, 1H),4.62-4.53 (m, 3H), 4.43-4.39 (m, 2H), 3.91-3.87 (m, 2H), 2.63-2.53 (m,2H), 2.39 (m, 1H), 2.12 (a, 3H), 1.89 (m, 1H); ES⁺ MS: 466 (M+1).

Example Z-27(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylsulfonyl)ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

To a solution of(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-[2-(methylthio)ethyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(20 mg, 0.04 mmol) in dichloromethane (5 mL) at 0° C. was added m-CPBA(20 mg, 70%, 0.082 mmol). The resultant solution was allowed to warm asthe bath warmed and stirred a total of 3 h. The reaction was quenched bythe addition of Na₂S₂O₃ (aq) and sodium bicarbonate. The layers wereseparated and the organic layer washed with brine. The aqueous layer wasextracted with dichloromethane and the combined organics dried overNa₂SO₄. Filtration and concentration provided(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-[2-(methylsulfonyl)ethyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(26 mg, 99%) as a white solid. This material was hydrogenated in asecond step as described in example Z-1 to give(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[2-(methylsulfonyl)ethyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(22 mg, 99%) as a white solid. ¹H NMR (CDCl₃) δ 11.00 (br, 1H), 10.16(s, 1H), 8.33 (s, 1H), 7.36 (m, 1H), 6.81 (m, 2H), 5.42 (m, 1H), 4.62(m, 3H), 4.41 (m, 2H), 3.93 (m, 2H), 3.31 (m, 2H), 2.98 (s, 3H), 2.40(m, 1H), 2.28 (m, 1H); ES⁺ MS: 498 (M+1).

Example Z-28(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-(1H-indol-3-ylmethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-1. 16a (43 mg, 0.09 mmol) and(2S)-2-amino-3-(1H-indol-3-yl)-1-propanol (100 mg, 0.52 mmol) werereacted in 1,2-dichloroethane (5 mL) with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-(1H-indol-3-ylmethyl)-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(36 mg, 64%). This material was hydrogenated in a second step asdescribed in example Z-1 to give(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy3-(1H-indol-3ylmethyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(29 mg, 95%) as a white solid. ¹H NMR (CDCl₃/CD₃OD) δ 10.34 (m, 1H),8.98 (br, 1H), 8.24 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.32 (m, 2H),7.15-7.01 (m, 3H), 6.78 (m, 2H), 4.94 (d, J=6.8 Hz, 1H), 4.71 (d, J=5.6Hz, 1H), 4.59 (m, 2H), 4.85 (d, J=10.4 Hz, 1H), 4.22 (m, 1H), 3.99 (m,1H), 3.81 (m, 1H), 3.40 (dd, J=13.6, 11.6 Hz, 1H), 3.18 (dd, J=14.0, 8.4Hz, 1H); ES⁺ MS: 521 (M+1).

Example Z-29(4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) (2R)-2-({[(1,1-Dimethylethyl)oxy]carbonyl}amino)propylmethanesulfonate, To a stirred solution of 1,1-dimethylethyl[(1R)-2-hydroxy-1-methylethyl]carbamate (5.00 g, 28.5 mmol) andtriethylamine (5.92 mL, 42.9 mmol) in CH₂Cl₂ (30 mL) cooled to 0° C. andunder a nitrogen atmosphere was added dropwise a solution ofmethanesulfonyl chloride (2.43 mL, 31.5 mmol) in CH₂Cl₂ (25 mL).Stirring was continued for 20 minutes at 0° C., after which time thereaction was judged complete by TLC analysis (1:1 hexanes/EtOAc). Thesolution was poured into water and the layers were separated. Theorganic phase was washed with 0.1 N HCl and then with 5% NaHCO₃, driedover Na₂SO₄, filtered and concentrated to give(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl methanesulfonate(7.08 g, 98%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.23 (d, J=6.8Hz, 3H), 1.44 (s, OH), 3.03 (a, 3H), 3.97 (m, 1H), 4.15 (dd, J=4.2, 9.8Hz, 1H), 4.21 (m, 1H), 4.61 (br s, 1H).

b) 1,1-Dimethylethyl [(1R)-2-cyano-1-methylethyl]carbamate. To a stirredsolution of (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propylmethanesulfonate (7.08 g, 27.9 mmol) in DMSO (50 mL) was added NaCN(8.78 g, 84.0 mmol). The solution was stirred at 70° C. for 2 hours,over which time the formation of a precipitate was observed. Aftercooling at room temperature, water was added and the mixture wasextracted with Et₅₀. The ethereal layers were washed with a brinesolution, dried over Na₂SO₄, filtered and concentrated to give1,1-dimethylethyl [(1R)-2-cyano-1-methylethyl]carbamate (3.81 g, 73%) asa pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 1.30 (d, J=6.8 Hz, 3H),1.42 (s, 9H), 2.51 (dd, J=3.8, 16.6 Hz, 1H), 2.73 (m, 1H), 3.93 (m, 1H),4.63 (br s, 1H).

c) 1,1-Dimethylethyl [(1R)-3-amino-1-methylpropyl]carbamate. A solutionof 1,1-dimethylethyl [(1R)-2-cyano-1-methylethyl]carbamate (1.30 g, 7.1mmol) in ethanol saturated with anhydrous ammonia was treated withRaney-Ni (1.5 mL of 50% aq. Suspension) and 55 psi of H₂ overnight. Themixture was filtered through Celite and the filtrate was concentrated invacuo. The residue was purified by flash chromatography (80:19:1CH₂Cl₂/MeOH/NH₄OH (87%) gradient elution) through a short plug of silicagel to give 1,1-dimethylethyl [(1R)-8-amino-1-methylpropyl]carbamate(1.37 g, 100%) as a clear oil that solidified. ¹H NMR (400 MHz, CDCl₃) δ1.14 (d, J=6.8 Hz, 3H), 1.48-1.62 (m, 13H), 2.76 (m, 2H), 3.77 (m, 1H),4.57 (m, 1H).

d) 1,1-Dimethylethyl{(1R)-1-methyl-3-[(2-methylpropyl)amino]propyl}carbamate.1,1-dimethylethyl [(1R)-3-amino-1-methylpropyl]carbamate (0.320 g, 1.70mmol), isobutyraldehyde (150 μL, 1.62 mmol), and sodiumtriacetoxyborohydride (0.512 g, 2.42 mmol) were stirred in anhydrousdichloroethane (10 mL) at ambient temperature overnight. The reactionwas quenched by the addition of saturated NaHCO₃ and then extracted withdichloromethane. The combined extracts were washed with water, driedover Na₂SO₄, filtered and concentrated. The residue was purified byflash chromatography (80:19:1 CH₂Cl₂/MeOH/NH₄OH (37%) gradient elution)through a short plug of silica gel to afford 1,1-dimethylethyl{(1R)-1-methyl-3-[(2-methylpropyl)amino]propyl}carbamate (0.158 g, 40%)as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 0.90 (d, J=6.4 Hz, 6H), 1.13(d, J=6.4 Hz, 3H), 1.42-1.51 (m, 11H), 1.67-1.75 (m, 2H), 2.83-2.42 (m,2H), 2.58-2.72 (m, 2H), 3.72 (m, 1H), 5.20 (m, 1H).

e) [(3R)-3-Aminobutyl](2-methylpropyl)amine. An ice cold solution of1,1-dimethylethyl{(1R)-1-methyl-3-[(2-methylpropyl)amino]propyl}carbamate (0.158 g, 0.65mmol) in THF (8 mL) was treated with 4 N HCl (aq) (2 mL) and thenstirred at room temperature for 2 h. The mixture was concentrated invacuo to give [(3R)-3-aminobutyl](2-methylpropyl)amine dihydrochloride.The HCl salt was then dissolved in dichloromethane and a minimal amountof methanol and treated with solid supported carbonate resin(MP-Carbonate, Argonaut Technologies). After 30 minutes, the solutionwas filtered through a fritted tube and the solvents removed carefullyin vacuo to give [(3R)-3-aminobutyl](2-methylpropyl)amine (65 mg). ¹HNMR (400 MHz, CDCl₃) δ 0.88 (d, J=6.0 Hz, 6H), 1.06 (d, J=5.6 Hz, 3H),1.23-1.53 (m, 5H), 1.71-1.74 (m, 1H), 2.89 (m, 2H), 2.65 (m, 2H), 2.97(m, 1H).

f)(4R,12aR)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16 (40 mg, 0.09 mmol) and[(3R)-3-aminobutyl](2-methylpropyl)amine (65 mg, 0.45 mmol) were reactedin dichloromethane (2 mL) with acetic acid to give(4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(29 mg, 60%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(18 mg, 75%) as a tan solid. ¹H NMR (400 MHz, CDCl₃) δ 0.77 (d, J=6.4Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 1.32 (d, J=7.2 Hz), 1.45-1.49 (m, 1H),1.57-1.67 (m, 1H), 2.08-2.12 (m, 2H), 2.21-2.27 (m, 1H), 2.73-2.79 (m,1H), 2.87-2.92 (m, 1H), 4.16-4.24 (m, 2H), 4.45 (s, 1H), 4.54-4.64 (m,2H), 4.96-4.99 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.82 (m, 211), 8.27 (s,1H), 10.46 (e, 1H), 12.55 (s, 1H); ES⁺ MS: 456 (M+1).

Example Z-30(4R,12aR)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3R)-8-Aminobutyl](1-methylethyl)amine. The free diamine wasprepared in a similar manner as described in example Z-20. ¹H NMR (400MHz, CDCl₃) δ 1.04 (d, J=6.4 Hz, 6H), 1.06 (d, J=6.4 Hz, 3H), 1.41-1.58(m, 5H), 2.62-2.66 (m, 2H), 2.74-2.80 (m, 1H), 2.92-3.00 (m, 1H).

b)(4R,12aR)—N-[(4-Fluorophenyl)methyl]-7hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16 (40 mg, 0.088 mmol) and[(3R)-3-aminobutyl](1-methylethyl)amine (78 mg, 0.60 mmol) were reactedin dichloromethane (2 mL) with acetic acid to give(4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(26 mg, 56%). This material was hydrogenated in a second stop asdescribed in example Z-2 to give(4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(21 mg, 90%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.01 (d,J=5.6 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H), 1.31 (d, J=6.8 Hz, 3H), 1.57 (m,1H), 1.98 (m, 1H), 2.70-2.82 (m, 2H), 3.15 (m, 1H), 4.15-4.19 (m, 1H),4.30 (m, 1H), 4.48 (s, 1H), 4.54-4.59 (m, 2H), 4.97 (m, 1H), 6.98 (m,2H), 7.29-7.32 (m, 2H), 8.27 (s, 1H), 10.49 (s, 1H), 12.52 (s, 1H).

Example Z-31(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) 1,1-Dimethylethyl [(1S)-2-cyano-1-methylethyl]carbamate. The nitrilewas prepared in two steps using a modified procedure as described inexample Z-29. To a stirred solution of(2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)propyl methanesulfonate(8.40 g, 33.2 mmol) in DMSO (50 mL) and KCN (6.51 g, 100.0 mmol) cooledto 0° C. was added 18-crown-6 (9.05 g, 84.3 mmol). The solution wasallowed to warm to room temperature and then heated to 70° C. for 1hour. After cooling at room temperature, water was added and the mixturewas extracted with Et₂O. The ethereal layers were washed with a brinesolution, dried over Na₂SO₄, filtered and concentrated to give1,1-dimethylethyl [(1S)-2-cyano-1-methylethyl]carbamate (5.37 g, 88%) asa pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 1.32 (d, J=6.8 Hz, 3H),1.44 (s, 9H), 2.52 (dd, J=4.0, 16.4 Hz, 1H), 2.74 (m, 1H), 3.95 (m, 1H),4.65 (br s, 1H).

b) [(3S)-3-Aminobutyl](2-methylpropyl)amine dihydrochloride was preparedin a similar manner as described in example Z-29. ¹H NMR (400 MHz,CDCl₃/CD₃OD) δ 0.99 (m, 6H), 1.34 (m, 3H), 2.13-2.27 (min, 3H), 2.76 (m,2H), 3.07 (m, 2H), 3.47 (m, 1H), 8.22 (m, 1H), 8.88 (m, <1H).

c)(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (80 mg, 0.17 mmol) and free based[(3S)-3-aminobutyl](2-methylpropyl)amine (107 mg, 0.74 mmol) werereacted in dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(76 mg, 76%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(39 mg, 80%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 0.76 (d,J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 1.32 (d, J=7.2 Hz, 3H), 1.45-1.50(m, 1H), 1.60-1.69 (m, 1), 2.03-2.12 (m, 2H), 2.21-2.27 (m, 1H),2.73-2.79 (m, 1H), 2.87-2.98 (m, 1H), 4.16-4.25 (m, 2H), 4.45 (s, 1H),4.57-4.68 (m, 2H), 4.96-5.01 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m,1H), 8.26 (s, 1H), 10.45 (s, 1H), 12.56 (s, 1H); ES⁺ MS: 475 (M+1).

Example Z-82(4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) 1,1-Dimethylethyl{(1S)-3-[(cyclopropylmethyl)amino]-1-methylpropyl}carbamate. Theprotected diamine was prepared using a modified procedure as describedin example Z-29. 1,1-dimethylethyl[(1S)-3-amino-1-methylpropyl]carbamate (0.293 g, 1.56 mmol),cyclopropane carboxaldehyde (96 μL, 1.30 mmol), and sodiumtriacetoxyborohydride (0.439 g, 2.07 mmol) were stirred in a 1:1 mixtureof anhydrous dichloroethane and tetrahydrofuran (10 mL) at ambienttemperature overnight. The reaction was quenched by the addition ofsaturated NaHCO₃ and then extracted with EtOAc. The combined extractswere washed with saturated NaHCO₃, then a solution of brine, dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography (80:19:1 CH₂Cl/MeOH/NH₄OH (37%) gradient elution) througha short plug of silica gel to afford 1,1-dimethylethyl{(1S)-3-[(cyclopropylmethyl)amino]-1-methylpropyl}carbamate (76 mg, 26%)as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 0.09-0.18 (m, 2H), 0.44-0.49(m, 2H), 0.92-0.95 (m, 1H), 1.14 (d, J=6.4 Hz, 3H), 1.43-1.70 (m, 12H),2.38-2.50 (m, 2H), 2.62-2.73 (m, 2H), 3.74 (m, 1H), 4.88 (m, 1H).

b) [(3S)-3-Aminobutyl](cyclopropylmethyl)amine dihydrochloride wasprepared in a similar manner as described in example Z-29. ¹H NMR (400MHz, CDCl₃/CD₃OD) δ 0.40 (m, 2H), 0.64 (m, 2H), 1.15 (m, 1H), 3.34 (m,3H), 2.12-2.25 (m, 2H), 2.82 (m, 2H), 8.08 (m, 2H), 3.47 (m, 1H), 8.25(br, <1H), 9.04 (br, <1H),

c)(4S,12aS)-1-(Cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (50 mg, 0.106 mmol) and free based[(3S)-3-aminobutyl](cyclopropylmethyl)amine (44 mg, 0.81 mmol) werereacted in dichloromethane (2 mL) with acetic acid to give(4S,12aS)-1-(cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(50 mg, 83%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)-1-(cyclopropylmethyl)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(23 mg, 56%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 0.11 (m,2H), 0.56-0.59 (m, 2H), 0.77 (m, 1H), 1.34 (d, J=7.2 Hz, 3H), 1.46-1.50(m, 1H), 2.04-2.13 (m, 1H), 2.80-2.34 (m, 1H), 2.46-2.51 (m, 1H),2.90-2.96 (m, 1H), 3.16-3.10 (m, 1H), 4.21-4.30 (m, 2H), 4.51 (s, 1H),4.58-4.67 (m, 2H), 5.00-5.05 (m, 1H), 6.76-6.82 (m, 2H), 7.31-7.37 (m,1H), 8.28 (s, 1H), 10.46 (s, 1H), 12.55 (br, 1H); ES⁺ MS: 473 (M+1).

Example Z-33(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-3-Aminobutyl](2-furanylmethyl)amine dihydrochloride wasprepared in a similar manner as described in example Z-32. ¹H NMR (400MHz, CDCl₃/CD₃OD) δ 1.27 (d, J=6.4 Hz, 3H), 1.96-2.05 (m, 1H), 2.14-2.19(m, 1H), 3.00-3.04 (m, 2H), 3.38-3.39 (m, 1H), 4.11-4.18 (m, 2H), 6.34(m, 1H), 6.59 (m, 1H), 7.40 (m, 1H), 8.18 (br, <1H), 9.41 (br, <1H).

b)(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (36 mg, 0.076 mmol) and free based[(3S)-3aminobutyl](2-furanylmethyl)amine (70 mg, 0.42 mmol) were reactedin dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-1-(2furanylmethyl)-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(82 mg, 70%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-1-(2-furanylmethyl)-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(20 mg, 76%), as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.24 (d,J=6.8 Hz, 3H), 1.45-1.49 (m, 1H), 2.04-2.13 (m, 1H), 2.77-2.82 (m, 1H),2.94-8.01 (m, 1H), 3.65 (d, J=15.6 Hz, 1H), 3.89 (d, J=16.0 Hz, 1H),4.27-4.31 (m, 1H), 4.39-4.41 (m, 1H), 4:49-4.63 (m, 1H), 4.58-4.66 (m,1H), 4.08-5.08 (m, 1H), 6.24 (m, 1H), 6.36 (m, 1H), 6.75-6.82 (m, 2H),7.31-7.39 (m, 1H), 7.40 (m, 1H), 8.26 (s, 1H), 10.47 (m, 1H), 12.50 (br,1H); ES⁺ MS: 499 (M+1).

Example Z-34(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(1,3-thiazol-2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-3-Aminobutyl](1,3-thiazol-2-ylmethyl)amine dihydrochloride wasprepared in a similar manner as described in example Z-32. ¹H NMR (400MHz, CDCl₃/CD₃OD) δ 1.28 (d, J=6.4 Hz, 3H), 2.05 (m, 1H), 2.17 (m, 1H),3.20 (m, 2H), 3.$0 (m, 1H), 4.51-4.58 (m, 2H), 7.52 (d, 1H), 7.82 (d,1H).

b)(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(1,3-thiazol-2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (35 mg, 0.074 mmol) and free based[(3S)-3-aminobutyl](1,3-thiazol-2-ylmethyl)amine wore reacted indichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1-(1,3-thiazol-2-ylmethyl)-1,2,8,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2a]pyrimidine-9-carboxamide(36 mg, 80%) as a film. This material was debenzylated in a second stepto in a manner similar to Z-26 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(1,3-thiazol-2-ylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(18 mg, 60%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.30 (d,J=7.2 Hz, 3H), 1.49-1.53 (m, 1H), 2.12-2.18 (m, 1H), 2.93-2.96 (m, 1H),3.07-3.13 (m, 1H), 3.99-4.08 (m, 1H), 4.18-4.17 (m, 1H), 4.24-4.27 (m,1H), 4.57-4.61 (m, 3H), 5.03-5.06 (m, 1H), 6.75-6.82 (m, 2H), 7.26 (m,1H), 7.31-7.87 (m, 2H), 7.76 (m, 1H), 7.94 (m, 1H), 10.40 (m, 1H), 12.48(m, 1H); ES⁺ MS: 516 (M+1).

Example Z-35racemic-(4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide

a)racemic-(4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide.racemic-cis-2-Hydroxymethyl-1-cyclohexylamine hydrochloride (24 mg,0.186 mmol) was dissolved in a dichloromethane solution containing asmall amount of methanol (to dissolve) and excess MP-Carbonate (ArgonautTechnologies) was added, the mixture was stirred for 30 minutes, and theMP-Carbonate was removed by filtration. The free amine solution wastransferred to a microwave vessel containing 16a (29 mg, 0.0617 mmol).One drop of glacial acetic acid was added and the solution was heatedfor 10 minutes at 140° C. The resultant solution was absorbed on celiteand the material was purified by silica gel chromatography (0-12%methanol/dichloromethane gradient elution) to yield the desired productas a white solid (18 mg, 58%). ¹H NMR (CDCl₃) δ 10.40 (m, 1H), 8.85 (s,1H), 7.60 (m, 2H), 7.34-7.26 (m, 4H), 6.80 (m, 2H), 5.35-5.23 (m, 2H),5.13 (m, 1H), 4.77 (m, 1H), 4.70 (m, 2H), 4.22 (dd, J=13.2, 3.2 Hz, 1H),4.07 (dd, J=13.2, 6.4, 1H), 3.96 (m, 1H), 3.76 (dd, J=11.2, 4.4, 1H),2.22 (m, 1H), 1.84 (m, 1H), 1.74-1.40 (m, 6H), 1.17 (m, 1H); ES⁺ MS: 550(M+1).

b)racemic-(4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide.racemic-(4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[3,2-a][3,1]benzoxazine-10-carboxamide(13 mg, 0.0236 mmol) was dissolved in tetrahydrofuran and 10 w.t. % Pd/C(13 mg) was added. Hydrogen was passed through the solution severaltimes and the mixture was stirred at 1 atm hydrogen for 18 hours untilthe reaction was determined complete by TLC (5%methanol/dichloromethane). The mixture was filtered through Celtite,eluting with methanol/chloroform and the filtrate was concentrated underreduced pressure and purified by HPLC to yield the title compound (7.3mg, 78%) ¹H NMR (CDCl3) δ 12.45 (m, 1H), 10.38 (s, 1H), 8.30 (s, 1H),7.32 (m, 1H), 6.83-6.76 (m, 2H), 5.28 (m, 1H), 4.75 (m, 1H), 4.63 (m,2H), 4.26 (m, 1H), 4.12-4.01 (m, 2H), 8.83 (m, 1H), 2.30 (m, 1H), 1.01(m, 1H), 1.80 (m, 1H), 1.67-1.40 (m, 5H), 1.20 (m, 1H); ES⁺ MS: 460(M+1).

Example Z-36racemic-(4aR,6a,14aR)—N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide

a)racemic-(4aR,6aR,14aS)—N-[(4-Fluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide.In a manner similar to that described in example Z-35, fromracemic-cis-2-Hydroxymethyl-1-cyclohexylamine hydrochloride (50 mg,0.303 mmol) and 16 (45 mg, 0.0995 mmol) was preparedracemic-(4aR,6aR,14aS)—N-[(4-fluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide(48 mg, 91%) as a white solid. ¹H NMR (CDCl₃) δ 10.42 (m, 1H), 8.37 (s,1H), 7.59 (m, 2H), 7.88-7.24 (m, 6H), 6.98 (m, 2H), 5.26-5.18 (m, 2H),5.07 (m, 1H), 4.74 (m, 1H), 4.62-4.51 (m, 2H), 4.20 (dd, J=13.6, 4 Hz,1H), 4.04 (m, 1H), 3.91 (m, 1H), 3.71 (dd, J=11.3, 4.8 Hz, 1H), 2.18 (m,1H), 1.82 (m, 1H), 1.78-1.63 (m, 2H), 1.62-1.56 (m, 2H), 1.48 (, 1H),1.38 (m, 1H), 1.14 (m, 1H); ES⁺ MS: 632 (M+1).

b)racemic-(4aR,6aR,14aS)—N-[(4-Fluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide.In a manner similar to that described in example Z-37, fromracemic-(4aR,6aR,14aS)—N-[(4-fluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide(37 mg, 0.0696 mmol) and 10 w.t. % Pd/C (3 mg) was prepared the titlecompound (18 mg, 58%) as a white solid after purification by HPLC. ¹HNMR (CDCl₃) δ 12.47 (s, 1H), 10.39 (m, 1H), 8.32 (s, 1H), 7.30 (m, 2H),6.98 (m, 2H), 5.22 (m, 1H), 4.74 (m, 1H), 4.58 (m, 2H), 4.28 (dd,J=13.2, 4 Hz, 1H), 4.12-3.98 (m, 2H), 3.81 (dd, J=11.6, 4.8 Hz, 1H),2.29 (m, 1H), 1.91-1.19 (m, 3H); ES⁺ MS: 442 (M+1).

Example Z-37racemic-(3S,4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-3-phenyl-1,3,4,4a,5.6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide

a)racemic-(3S,4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-3-phenyl-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide.In a manner similar to that described in example Z-35, fromracemic-[(1R,2S,5S)-2-amino-5-phenylcyclohexyl]methanol hydrochloride(32 mg, 0.160 mmol) and 16a (30 mg, 0.064 mmol) was preparedracemic-(3S,4aR,6aR,14aS)—N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-3-phenyl-12-[(phenylmethyl)oxy]-1,3,4,4a,6,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide(35 mg, 88%) as a white solid. ¹H NMR (CDCl₃) δ 10.41 (m, 1H), 8.38 (s,1H), 7.66 (m, 2H), 7.40-7.26 (m, 6H), 6.81 (m. 3H), 5.32-5.25 (m, 2H),5.17 (m, 1H), 4.89 (m, 1H), 4.66-4.62 (m, 2H), 4.26 (dd, J=13.6, 4 Hz,1H), 4.13-4.04 (m, 2H), 3.85 (dd, J=11.2, 4.4 Hz, 1H), 2.56 (m, 1H),2.37 (m, 1H), 2.03-1.64 (m, 6H); ES⁺ MS: 626 (M+1).

b)racemic-(3S,4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-12hydroxy-11,13-dioxo-3-phenyl-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide.racemic-(3S,4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-3-phenyl-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide(27 mg, 0.0432 mmol) was suspended in methanol, 10 w.t. % Pd/C (3 mg)was added and hydrogen was bubbled through the system several timesuntil the reaction was determined complete by TLC (5%methanol/dichloromethane). The suspension was filtered through Celiteeluting with methanol/chloroform and the filtrate was concentrated underreduced pressure and purified by HPLC to give the title compound (13 mg,57%) as a white solid. ¹H NMR (CDCl₃) δ 12.40 (br s, 1H), 10.37 (m, 1H),8.32 (s, 1H), 7.37-7.28 (m, 3H), 7.24-7.15 (m, 4H), 6.79 (m, 2H), 5.78(br s, 1H), 4.85 (m, 1H), 4.62 (m, 2H), 4.29 (m, 1H), 4.16-4.09 (m, 2H),3.02 (dd, J=11.6, 4.8 Hz, 1H), 2.58 (m, 1H), 2.46 (m, 1H), 2.07-1.64 (m,7H); ES⁺ MS: 536 (M+1).

Example Z-38 Sodiumracemic-(4aS,6aS,14aS)-10-({[(2,4difluorophenyl)methyl]amino}carbonyl)-6-(2-methylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazolin-12-olate

a) racemic-1,1-Dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate.racemic-[(1R,2S,5S)-2-Amino-5-phenylcyclohexyl]methanol hydrochloride(800 mg, 4.82 mmol) was dissolved in MeOH (40 mL) andbis(1,1-dimethylethyl) dicarbonate (1.16 g, 5.80 mmol) and triethylamine(4 mL, 28.92 mmol) were added and the mixture was stirred 18 hours atambient temperature. The solvents were removed under reduced pressure,ethyl acetate and aqueous saturated sodium bicarbonate were added andthe product was extracted with ethyl acetate. The combined organics weredried over sodium sulfate and the solvents were removed under reducedpressure. Purification by silica gel chromatography (9:1 hexanes: ethylacetate to ethyl acetate gradient elution) gave 1,1-dimethylethylracemic-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (934 mg, 85%) asa white solid. ¹H NMR (CDCl₃) δ 4.87 (m, 1H), 4.03-3.95 (m, 2H), 3.26(m, 1H), 8.15 (m, 1H), 1.73-1.48 (m, 5H), 1.38 (s, 9H), 1.27-1.15 (m,3H), 0.887 (m, 1H).

b) racemic-1,1-Dimethylethyl [(1S,2R)-2-Formylcyclohexyl]carbamate. To asolution of dimethylsulfoxide (0.2 mL, 2.88 mmol) in dichloromethane (8mL) at −78° C. was added oxalyl chloride (0.72 mL, 1.44 mmol) dropwise.The mixture was stirred minutes and racemic-1,1-dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (220 mg, 0.961 mmol) indichlormethane was added dropwise and stirred 10 minutes. Triethylamine(0.53 mL, 3.84 mmol) was added slowly and the reaction was stirred at−78° C. for one hour and allowed to warm to ambient temperature. Waterwas added and product was extracted with dichloromethane. The combinedorganics were washed with brine and dried over sodium sulfate. Removalof solvents under reduced pressure afforded racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (223 mg, quantitative) as a yellowoil. ¹H NMR (CDCl₃) δ 9.61 (s, 1H), 5.19 (m, 1H), 3.88 (m, 1H), 2.61 (m,1H), 1.85 (m, 1H), 1.63-1.49 (m, 4H), 1.37-1.16 (m, 12H).

c) racemic-1,1-dimethylethyl((1S,2S)-2-{[(2-Methylpropyl)amino]methyl}cyclohexyl)carbamate.racemic-1,1-Dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (223 mg,0.982 mmol) was dissolved in dichloroethane and 2-methylpropyl)amine(0.15 mL, 1.47 mmol) and sodium triacetoxyborohydride (290 mg, 1.87mmol) were added and the reaction was stirred at ambient temperature for18 hours. Aqueous sodium bicarbonate was added and the product wasextracted with dichloromethane. The combined extracts were dried oversodium sulfate and the solvents were removed under reduced pressure.Purification by silica gel chromatography (dichloromethane to 1%ammonium hydroxide 19% methanol 80% dichloromethane gradient elution)afforded racemic-1,1-dimethylethyl((1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclohexyl)carbamate (112 mg,40%) as a clear colorless oil. ¹H NMR (CDCl₃) δ 6.06 (br s, 1H), 3.76(br s, 1H), 2.63 (m, 1H), 2.48-2.37 (m, 2H), 2.25 (m, 1H), 1.81 (m, 1H),1.71-1.59 (m, 3H), 1.44-1.82 (m, 14H), 1.27-1.19 (m, 2H), 0.866 (m, 6H).

d) racemic-(1S,2S)-2-{[(2-Methylpropyl)amino]methyl}cyclohexanaminehydrochloride.

In a manner similar to that describe in example Z-3, step e, fromracemic-1,1-dimethylethyl((1S,2S)-2-{([(2-methylpropyl)amino]methyl}cyclohexyl)carbamate (112ing, 0.894 mmol) was prepared(1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclohexanamine hydrochloride(130 mg, >100%) as a white solid. ¹H NMR (methanol-d₄/CDCl₃) δ 8.68-8.28(m, 1H), 3.62 (br s, 1H), 3.26 (m, 1H), 2.83-2.78 (Cm, 3H), 2.54 (br s,1H), 2.12 (m, 1H), 1.82-1.66 (m, 3H), 1.53-1.89 (m, 5H), 0.96 (m, 6H),0.766 m, 1H).

e)racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-6-(2-methylpropyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.In a manner similar to that described in Z-35, fromracemic-(4S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclohexanaminehydrochloride (130 mg, 0.508 mmol) and 16a (55 mg, 0.117 mmol) waspreparedracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-(2-methylpropyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(44 mg, 62%) with a 12:1 d.r. ¹H NMR (CDCl₃) δ 10.46 (m, 1H), 8.88 (s,1H), 7.59 (m, 2H), 7.37-7.24 (m, 4H), 6.79 (m, 2H), 5.30-5.23 (m, 2H),4.75-4.56 (m, 3H), 4.23-4.09 (m, 3H), 2.69-2.66 (m, 2H), 2.21-1.98 (m,3H), 1.80 (m, 1H), 1.71-1.33 (m, 6H), 1.26-1.19 (m, 2H), 0.810 (m, 3H),0.720 (m, 3H); ES⁺ MS: 605 (M+1).

f)racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-methylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.In a manner similar to that described in example Z-37, fromracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)-methyl]-6-(2-methylpropyl)-11,13dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(39 mg, 0.064 mmol) and 10 w.t. % Pd/C (7 mg) was preparedracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-12-hydroxy-6-(2-methylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(36 mg, >100%) as a tan solid. ¹H NMR (CDCl₃) δ 12.60 (br s, 1H), 10.43(br s, 1H), 8.25 (s, 1H), 7.35 (m, 1H), 6.78 (m, 2H), 4.77 (m, 1H), 4.68(m, 2H), 4.49 (br s, 1H), 4.80-4.13 (m, 2H), 3.63-3.40 (m, 2H),2.88-2.71 (m, 2H), 2.82-2.21 (m, 2H), 2.05 (m, 1H), 1.88-1.11 (m, 7H),0.830 (m, 3H), 0.760 (m, 3 H); AP⁺ MS: 515 (M+1).

-   -   g) Sodium        racemic-(4aS,6aS,14aS)-10-({[(2,4-Difluorophenyl)methyl]amino}carbonyl)-6-(2-methyl        propyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazolin-12-olate.        In a manner similar to that described in example Z-1, from        racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-12-hydroxy-6-(2-methylpropyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,        5]pyrazino[1,2-a]quinazoline-10-carboxamide (87 mg, 0.071 mmol)        and 1 N sodium hydroxide (0.07 mL) the title compound was        prepared as a yellow solid (26 mg, 68%). ¹H NMR (DMSO-d₆) δ        10.73 (m, 1H), 7.94 (s, 1H), 7.82 (m, 1H), 7.19 (m, 1H), 7.00        (m, 1H), 4.59-4.41 (m, 3H), 4.28 (m, 2H), 4.14 (br s, 1H),        2.63-2.60 (m, 2H), 1.98-1.61 (m, 5H), 1.48-1.36 (m, 4H), 0.997        (m, S H), 0.760 (m, 3H), 0.660 (m, 2H); AP⁺ MS: 515 (M+1 of free        acid).

Example Z-30(6aR,7aS,11aS)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide& Example Z-40(6aS,7aS,11aS)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide

a)(6aR,7aS,11aS)—N-[(2,4-Difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamideand(6aS,7aS,11aS)—N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide.In a manner similar to that described in example Z-2, from[(1S,2S)-2-aminocyclohexyl]amine (122 mg, 1.07 mmol) and 16a (200 mg,0.426 mmol) was prepared(6aR,7aS,11aS)—N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide(158 mg) and(6aS,7aS,11aS)—N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide(10.6 mg) after separation of the diastereomers using silica gelchromatography (0-12% methanol/dichloromethane).(6aR,7aS,11aS)—N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide(major): ¹H NMR (CDCl3) δ 10.40 (m, 1H), 8.33 (a, 1H), 7.57 (m, 2H),7.40-7.25 (m, 4H), 6.81 (m, 2H), 5.32 (d, J=10 Hz, 1H), 5.13 (d, J=10Hz, 1H), 4.64-4.58 (m, 3H), 4.21 (dd, J=12.4, 3.2 Hz, 1H), 3.79 (m, 1H),3.04 (m, 1H), 2.73 (m, 1H), 2.53 (m, 1H), 2.01-1.70 (m, 4H), 1.36-1.24(m, 4H); ES⁺ MS: 535 (M+1).(6aS,7aS,11aS)—N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide(minor diastereomer): ¹H NMR (CDCl₃) δ 10.33 (m, 1H), 8.28 (s, 1H), 7.61(m, 2H), 7.89-7.28 (m, 3H), 6.79 (m, 2H), 5.29 (d, J=9.6 Hz, 1H), 5.05(d, J=9.6 Hz, 1H), 4.84 (m, 1H), 4.60 (m, 2H), 3.90-3.84 (m, 2H), 3.07(m, 1H), 2.75 (m, 1H), 2.49 (m, 1H), 2.07 (m, 1H), 1.00-1.51 (m, 4H),1.33-1.19 (m, 4H); MS data matches that of its diastereomer.

b) (For example Z-39),(6aR,7aS,11aS)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13dioxo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide.In a manner similar to that described in example Z-37, from the minordiastereomer prepared in step a(6aS,7aS,11aS)—N-[(2,4-difluorophenyl)methyl]-2,13-dioxo-1-[(phenylmethyl)oxy]-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide(7 mg, 0.0131 mmol) and 10 w.t. % Pd/C (catalytic amount) was prepared(6aR,7aS,11aS)—N-[(2,4-difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide(2.8 mg, 48%) after purification by HPLC. ¹H NMR (CDCl₃) δ 12.15 (br s,1H), 10.42 (br s, 1H), 8.31 (s, 1H), 7.86 (m, 1H), 6.80 (m, 2H), 5.01(m, 1H), 4.63 (m, 2H), 4.16 (m, 1H), 3.96 (m, 1H), 3.06-2.03 (m, 2H),2.61 (m, 1H), 2.18 (m, 1H), 1.93 (m, 1H), 1.60-1.13 (m, 4H),0.8938-0.840 (m, 2H); ES⁺ MS: 445 (M+1).

c) (For example Z-40).(6aS,7aS,11aS)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamide.In a manner similar to that described in example Z-87, from the majordiastereomer (80 mg, 0.0561 mmol) prepared in step a and 10 w.t. % Pd/C(catalytic amount),(6aS,7aS,11aS)—N-[(2,4-Difluorophenyl)methyl]-1-hydroxy-2,13-dioxo-2,6a,7,7a,8,9,10,11,11a,13-decahydro-6H-pyrido[1′,2′:4,5]pyrazino[1,2-a]benzimidazole-3-carboxamidewas prepared as a white solid (15 mg, 60%) after purification by HPLC.¹H NMR (methanol-d4/CDCl₃) δ 10.41 (m, 1H), 8.25 (e, 1H), 7.30 (m, 1H),6.77 (m, 2H), 4.77 (m, 1H), 4.57 (m, 2H), 4.45 (m, 1H), 3.91 (m, 1H),3.12 (m, 1H), 2.67 (m, 1H), 2.12 (m, 1H), 1.87-1.84 (m, 2H), 1.47-1.33(m, 4H); ES⁺ MS: 445 (M+1).

Example Z-41(5aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12dioxo-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide

a)(5aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)oxy]-1,2,3,4,6a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide.In a manner similar to that described in example Z-18, from 16a (50 mg,0.108 mmol) and [(2S)-2-piperidinylmethyl]amine hydrochloride (60 mg,0.260 mmol, made in a similar manner as described in example Z-18) wasprepared(3aS,14aS)—N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)oxy]-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide(40 mg, 78%). ¹H NMR (CDCl₃) δ 10.43 (m, 1H), 8.38 (s, 1H), 7.59 (m,2H), 7.59-7.25 (m, 4H), 6.81 (m, 2H), 5.38 (d, J=10 Hz, 1H), 6.19 (d,J=10 Hz, 1H), 4.65-4.62 (m, 2H), 4.20 (dd, J=12, 2.8 Hz, 1H), 4.00 (dd,J=12.4, 2.8 Hz, 1H), 3.85 (m, 1H), 3.74 (m, 1H), 3.27 (m, 1H), 2.99 (m,1H), 2.43 (m, 1H), 2.24 (m, 1H), 1.94-1.87 (m, 2H), 1.77-1.68 (m, 2H),1.39-1.24 (m, 2H); ES⁺ MS: 585 (M+1).

b)(5aS,14aS)—N-[(2,4-Difluorophenyl)ethyl)methyl-11-hydroxy-10,12-dioxo-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide.In a manner similar to that described in example Z-37, from(5aS,14aS)—N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)oxy]-1,2,3,4,5a,6,10,12,14,14a-decahydropyrido[1,2-a]pyrido[1′,2′:3,4]imidazo[1,2-d]pyrazine-9-carboxamide(18 mg, 0.0337 mmol) and 10 w.t. % Pd/C (catalytic amount) was preparedthe title compound as a white solid (13 mg, 87%) after purification byHPLC, 1H NMR (CDCl₃) δ 11.71 (br s, 1H), 10.36 (br s, 1H), 8.31 (s, 1H),7.34 (m, 1H), 6.78 (m, 2H), 4.64-4.57 (m, 2H), 4.28 (m, 1H), 4.12 (m,1H), 3.92-3.89 (m, 2H), 3.22 (m, 1H), 3.04 (m, 1H), 2.49 (m, 1H), 2.28(m, 1H), 1.97-1.89 (m, 2H), 1.78 (m, 1H), 1.66-1.60 (m, 2H), 1.43-1.36(m, 2H); ES⁺ MS: 445 (M+1).

Example Z-42(4aR,14aR)—N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide

a) Phenylmethyl (2R)-2-(hydroxymethyl) 1-piperidinecarboxylate. In amanner similar to that described in example Z-3a, from(2R)-1-{[(phenylmethyl)oxy]carbonyl}-2-piperidinecarboxylic acid (4.93g, 18.75 mmol) was prepared phenylmethyl(2R)-2-(hydroxymethyl)-1-piperidinecarboxylate (2.24 g, 48%) as an oilthat solidified upon standing to a white solid. ¹H NMR (CDCl₃) δ7.36-7.26 (m, 6H), 5.18-5.10 (m, 2H), 4.37 (m, 1H), 4.03 (m, 1H), 3.84(, m, 1H), 8.63 (m, 1H), 2.06 (br s, 1H), 1.71-1.42 (m, 6H).

b) Phenylmethyl (2R)-2-(cyanomethyl)-1-piperidinecarboxylate. In amanner similar to that described in example Z-3b, from phenylmethyl(2R)-2-(hydroxymethyl)-1-piperidinecarboxylate (1.09 g, 4.38 mmol) wasprepared phenylmethyl(2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-piperidinecarboxylate(1.05 g, 59% impure with uncharacterized byproduct) as a clear colorlessoil after purification using silica gel chromatography (10-100% ethylacetate-hexanes). It is necessary to use this material in the next stepas soon as possible or yields deteriorate dramatically. In a mannersimilar to that described in example Z-3c, from phenylmethyl(2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-piperidinecarboxylate(1.06 g, 2.61 mmol) and sodium cyanide (388 mg, 7.82 mmol) was preparedphenylmethyl (2R)-2-(cyanomethyl)-1-piperidinecarboxylate (171 mg, 25%)as a yellow oil. 1H NMR (CDCl₃) δ 7.35-7.29 (m, 5H), 5.13 (s, 2H), 4.65(m, 1H), 4.10 (m, 1H), 2.96 (m, 1H), 2.60 (m, 2H), 1.82-1.67 (m, 4H),1.54-1.390 (m, 2H).

d) Phenylmethyl (2R)-2-(2-aminoethyl)-1-piperidinecarboxylate. In amanner similar to that described in example Z-3d, from phenylmethyl(2R)-2-(cyanomethyl)-1-piperidinecarboxylate (171 mg, 0.6683 mmol) wasprepared phenylmethyl (2R)-2-(2-aminoethyl)-1-piperidinecarboxylate (119mg, 68%) as a clear colorless residue. ¹H NMR (CDCl₃) δ 7.82-7.25 (m,5H), 5.08 (m, 2H), 4.89 (br s, 1H), 4.01 (br s, 1H), 2.78 (m, 1H),2.60-2.56 (m, 2H), 1.95-1.86 (m, 3H), 1.63-1.85 (m, 6H).

e) (2S)-[(2R) 2-Piperidinyl]ethyl)amine. Phenylmethyl(2R)-2-(2-aminoethyl)-1-piperidinecarboxylate (119 mg, 0.454 mmol) wasdissolved in methanol and 10 w.t. % Pd/C (120 mg) was added. Hydrogenwas bubbled through the solution for 15 minutes and the reaction wasstirred under 1 atm hydrogen for 18 hours until determined complete byTLC (1% ammonium hydroxide 19% methanol 80% dichloromethane). Thesuspension was filtered through Celite eluting with methanol and thefiltrate was carefully concentrated under reduce pressure to yield aclear colorless liquid (58 mg, quantitative). ¹H NMR (CDCl₃) δ 2.00 (m,1H), 2.71-2.66 (m, 2H), 2.57-2.48 (m, 2H), 1.72 (m, 1H), 1.61-1.52 (m,2H), 1.48-1.42 (m, 2H), 1.35-1.25 (m, 2H), 1.05 (m, 1H).

f)(4aR,14aR)—N-[(2,4-Difluorophenyl)methyl]-8,10-dioxo-9-[(phenylmethyl)oxy]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide.In a manner similar to that described in example Z-35, from 16a (50 mg,0.106 mmol) and (2-[(2R)-2-piperidinyl]ethyl)amine (58 mg, 0.454 mmol)was prepared(4aR,14aR)—N-[(2,4-difluorophenyl)methyl]-8,10-dioxo-9-[(phenylmethyl)oxy]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide(47 mg, 81%). ¹H NMR (CDCl₃) δ 10.50 (br s, 1H), 8.88 (s, 1H), 7.60 (s,2H), 7.88-7.24 (m, 4H), 6.80 (m, 2H), 5.29-5.22 (m, 2H), 4.66-4.56 (m,3H), 4.80 (m, 1H), 4.10 (m, 1H), 3.78 (br s, 1H), 2.86-2.80 (m, 2H),2.18 (br s, 1H), 1.94 (m, 1H), 1.68-1.36 (m, 6H), 1.23 (br s, 2H); ES⁺MS: 549 (M+1).

g)(4aR,14aR)—N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide.In a manner similar to that described in example Z-87, from(4aR,14aR)—N-[(2,4-difluorophenyl)methyl]-8,10-dioxo-9-[(phenylmethyl)oxy]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide(47 mg, 0.0857 mmol) and a catalytic amount of 10 w.t. % Pd/C wasprepared the title compound as a white solid (10 mg, 64%) afterpurification by HPLC. ¹H NMR (CDCl₃) δ 10.40 (m, 1H), 8.29 (s, 1H), 7.34(m, 1H), 6.79 (m, 2H), 4.67-4.56 (m, 3H), 4.41 (m, 1H), 4.20 (m, 1H),3.93 (s, 1H), 2.94-2.87 (m, 2H), 2.28 (br s, 1H), 2.01 (m, 1H),1.68-1.54 (m, 4H), 1.44 (m, 1H), 1.29-1.28 (m, 3H), 0.850 (m, 1H); ES⁺MS: 459 (M+1).

Example Z-43(4R,12aR)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3-R)-3-Aminobutyl](3-methylbutyl)amine dihydrochloride was preparedin a similar manner as described in example Z-32. ¹H NMR (400 MHz,CDCl₃/CD₃OD) δ 0.87 (d, J=5.2 Hz, 6H), 1.32 (m, 3H), 1.61 (m, 3H),2.10-2.20 (m, 2H), 2.00-3.04 (m, 4H), 3.45 (m, 1H), 8.23 (br, <1H), 8.96(br, <1H).

b)(4R,12aR)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (40 mg, 0.086 mmol) and free[(3R)-3-aminobutyl](3-methylbutyl)amine (46 mg, 0.35 mmol) were reactedin dichloromethane (2 mL) with acetic acid to give(4R,12aR)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(3-methylbutyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(44 mg, 90%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4R,12aR)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(8-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(11 mg, 30%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 0.84 (d,J=6.8 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 1.24-1.86 (m, 5H), 1.47-1.53 (m,2H), 2.02-2.11 (m, 1H), 2.36-2.43 (m, 1H), 2.54-2.61 (m, 1H), 2.77-2.92(m, 2H), 4.16-4.26 (m, 2H), 4.44 (m, 1H), 4.62-4.64 (m, 2H), 4.95-5.02(m, 1H), 6.75-6.81 (m, 2H), 7.81-7.37 (m, 1H), 8.27 (s, 1H), 10.43 (m,1H), 12.54 (s, 1H); ES⁺ MS: 480 (M+1).

Example Z-44(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-8-Aminobutyl](1-methylethyl)amine dihydrochloride was preparedin a similar manner as described in example Z-29. ¹H NMR (400 MHz,CDCl₃/CD₃OD) δ 1.20-1.25 (m, OH), 1.93-2.02 (m, 2H), 2.92 (m, 2H),8.20-3.29 (m, 2H), 8.04 (br, <1H), 8.64 (br, <1H).

b)(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (60 mg, 0.13 mmol) and free based[(3S)-3-aminobutyl](1-methylethyl)amine (55 mg, 0.42 mmol) were reactedin dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(40 mg, 57%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(17 mg, 50%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.02 (d,J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.33 (d, J=7.2 Hz, 3H), 1.55-1.58(m, 1H), 1.94-2.03 (m, 1H), 2.70-2.77 (m, 1H), 2.81-2.86 (m, 1H),3.11-3.18 (m, 1H), 4.17 (dd, J=3.0, 13.8 Hz, 1H), 4.32 (dd, J=3.2, 14.0Hz, 1H), 4.48 (m, 1H), 4.59-4.69 (m, 2H), 4.97-5.00 (m, 1H), 6.77-6.83(m, 2H), 7.33-7.39 (m, 1H), 8.28 (s, 1H), 10.50 (m, 1H), 12.55 (s, 1H);ES⁺ MS: 461 (M+1).

Example Z-45(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-3-Aminobutyl](3-methylbutyl)amine dihydrochloride was preparedin a similar manner as described in example Z-82. ¹H NMR (400 MHz,CDCl₃/CD₃OD) δ 0.86 (d, J=5.6 Hz, 6H), 1.27 (d, J=6.0 Hz, 3H), 1.58 (m,3H), 2.03-2.14 (m, 2H), 2.87-2.09 (m, 4H), 8.88 (m, 1H), 8.15 (br, <1H),8.87 (br, <1H).

b)(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7hydroxy-4-methyl-1-(3-methylbutyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (0.100 g, 0.21 mmol) and free based[(3S)-3-aminobutyl](3-methylbutyl)amino (0.104 g, 0.66 mmol) werereacted in dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-1-(3-methylbutyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2a]pyrimidine-9-carboxamide(88 mg, 72%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-(3-methylbutyl)6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(55 mg, 74%). ¹H NMR (400 MHz, CDCl₃) δ 0.84 (d, J=6.4 Hz, 3H), 0.85 (d,J=6.4 Hz, 3H), 1.24-1.37 (m, 5H), 1.45-1.53 (m, 2H), 2.02-2.11 (m, 1H),2.37-2.44 (m, 1H), 2.66-2.68 (m, 1H), 2.80-2.92 (m, 2H), 4.22-4.20 (m,2H), 4.45 (s, 1H), 4.62-4.63 (m, 2H), 4.97-5.00 (m, 1H), 6.75-6.82 (m,2H), 7.81-7.87 (m, 1H), 8.87 (s, 1H), 10.48 (m, 1H), 12.53 (br, 1H); ES⁺MS: 489 (M+1).

Example Z-46 (4S,12aS)—N-[(2,4-Difluorophenyl)methyl7-hydroxy-4-methyl-6,8-dioxo-1-(8-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]]pyrimidine-9-carboxamide

a) 1,1-Dimethylethyl{(1S)-1methyl-3-[(3-pyridinylmethyl)amino]propyl}carbamate. Theprotected diamine was prepared using a modified procedure as describedin example Z-32. A solution of 1,1-dimethylethyl[(1S)-3-amino-1-methylpropyl]carbamate (0.206 g, 1.6 mmol) and3-pyridinecarboxaldehyde (120 μL, 1.3 mmol) in a 1:1 mixture ofanhydrous dichloroethane and tetrahydrofuran (10 mL) was treated withacetic acid (374 μL, 6.6 mmol) and stirred for 80 minutes. Sodiumtriacetoxyborohydride (0.444 g, 2.1 mmol) was added and the solution wasstirred for 2 hours. The resultant was subjected to a workup andpurification procedure as described in example Z-32 to give1,1-dimethylethyl {(1S)-1-methyl38-[(3pyridinylmethyl)amino]propyl}carbamate (0.245 g, 66%) as a clearoil. ¹H NMR (400 MHz, CDCl₃) δ 1.12 (d, J=6.4 Hz, 3H), 1.42 (a, 9H),1.46-1.54 (m, 1H), 1.68 (m, 1H), 2.61-2.75 (m, 2H), 3.73-3.80 (m, 3H),4.86 (m, 1H), 7.22-7.24 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 8.48 (m, 1H),8.53 (m, 1H).

b) [(3S)-3Aminobutyl](8-pyridinylmethyl)amine dihydrochloride wasprepared in a similar manner as described in example Z-29.

c)(4S,12aS)—N-[(2,4*Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(3-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (60 mg, 0.13 mmol) and free based[(9S)-3-aminobutyl](3-pyridinylmethyl)amine (83 mg, 0.47 mmol) werereacted in dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1-(3-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(72 mg, 95%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7hydroxy-4-methyl-6,8-dioxo-1-(3-pyridinylmethyl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(34 mg, 56%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.87 (d,J=6.8 Hz, 3H), 1.48-1.47 (m, 1H), 2.12 (m, 1H), 2.60-2.02 (m, 2H), 3.53(d, J=14.0 Hz, 1H), 3.82 (d, J=14.4 Hz, 1H), 4.23-4.31 (m, 2H),4.55-4.64 (m, 3H), 5.06-5.11 (m, 1H), 6.75-6.82 (m, 2H), 7.20-7.23 (m,1H), 7.31-7.36 (m, 1H), 7.50 (m, 1H), 7.92 (s, 1H), 8.48 (s, 1H), 10.39(m, 1H), 12.5 (br, 1H); ES⁺ MS: 510 (M+1).

Example Z-47(4S,12aS)-1-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) 1,1-Dimethylethyl [(1S)-1methyl-3-oxopropyl]carbamate. To a stirredsolution of 1,1-dimethylethyl [(1S)-2-cyano-1-methylethyl]carbamate(0.656 g, 3.56 mmol) in anhydrous ether cooled to −40° C. was addeddropwise a 1.0 M solution of diisobutylaluminum hydride in hexanes (14.2mL, 14.2 mmol) over 20 minutes.

Stirring was continued at this temperature for an additional 20 minutes.The yellow solution was quenched with Rochelle's salt and the resultantstirred at room temperature for 1 hour. The solids were filtered offthrough celite and rinsed with EtOAc. The organics were washed withbrine, concentrated, and flash chromatographed (10-100% EtOAc/hexanes)to give 1,1-dimethylethyl [(1S)-1-methyl-3-oxopropyl]carbamate (0.193 g,30%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 1.22 (d, J=6.8 Hz, 3H),1.41 (s, OH), 2.58-2.65 (m, 2H), 4.08-4.18 (m, 1H), 4.68 (m, 1H),9.74-9.75 (m, 1H).

b) 1,1-Dimethylethyl[(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate. The protecteddiamine was prepared using a modified procedure as described in exampleZ-32. A solution of 1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (0.178 g, 0.95 mmol) andcyclopropylamine (197 μL, 2.86 mmol) in anhydrous dichloroethane (10 mL)was treated with acetic acid (272 μL, 4.8 mmol) and stirred for 80minutes. Sodium triacetoxyborohydride (0.444 g, 2.1 mmol) was added andthe solution was stirred for 20 hours. The resultant was subjected to aworkup and purification procedure as described in example Z-32 to give1,1-dimethylethyl [(1S)-3-(cyclopropylamino)-1-methylpropyl]carbamate(0.186 g, 63%) as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ 0.32-0.42 (m,4H), 1.12 (d, J=6.8 Hz, 3H), 1.89-1.51 (m, 10H), 1.58-1.02 (m, 2H),2.05-2.10 (m, 1H), 2.67-2.80 (m, 2H), 8.71 (m, 1H), 4.78 (m, 1H).

c) [(3 S3-Aminobutyl]cyclopropylamine dihydrochloride was prepared in asimilar manner as described in example Z-20. ¹H NMR (400 MHz,CDCl₃/CD₃OD) δ 0.70-0.75 (m, 2H), 9.90-0.04 (m, 2H), 1.18 (d, J=6.8 Hz,3H), 1.84-1.94 (m, 1H), 1.97-2.05 (m, 1H), 2.49-2.54 (m, 1H), 2.90-3.04(m, 2H), 3.28-3.28 (m, 1H).

d) (4S,12aS)1-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (80 mg, 0.37 mmol) and free based[(3S)-3-aminobutyl]cyclopropylamine (75 mg, 0.59 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(4S,12aS)-1-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-4methyl-6,8dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(74 mg, 80%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)-1-cyclopropyl-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(32 mg, 52%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 0.87-0.54(m, 3H), 0.64-0.70 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.45-1.49 (m, 1H),1.76-1.80 (m, 1H), 2.03-2.12 (m, 1H), 2.86-2.03 (m, 1H), 2.00-3.04 (m,1H), 4.30 (dd, J=4.0, 13.6 Hz, 1H), 4.49-4.67 (m, 4H), 5.00-5.07 (m,1H), 6.75-6.82 (m, 2H), 7.32-7.36 (m, 1H), 8.28 (s, 1H), 10.49 (m, 1H),12.63 (s, 1H); ES⁺ MS: 459 (M+1).

Example Z-48(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-8-Aminobutyl][2-(methyloxy)ethyl]amine dihydrochloride. Theprotected diamine, 1,1-dimethylethyl((1S)-1-methyl-3-{[2-(methyloxy)ethyl]amino}propyl)carbamate wasprepared in a similar manner as described in example Z-47. Subsequently,[(3S)-3-aminobutyl][2-(methyloxy)ethyl]amine dihydrochloride wasprepared in a similar manner as described in example Z-29, ¹H NMR (400MHz, CDCl₃/CD₃OD) δ 1.21 (d, J=5.6 Hz, 3H), 1.93 (m, 1H), 2.04 (m, 1H),2.08-3.05 (m, 4H), 3.22 (m, 2H), 3.26-3.31 (m, 4H), 8.06 (br, <1H), 8.81(br, <1H).

b) (4 S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl1-[2-(methyloxy)ethyl]6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (60 mg, 0.18 mmol) and free based[(3S)-3-aminobutyl][2-(methyloxy)ethyl]amine (53 mg, 0.37 mmol) werereacted in dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl)methyl-4methyl-12-(methyloxy)ethyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(47 mg, 63%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(88 mg, 97%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 1.34 (d,J=7.2 Hz, 3H), 1.49 (m, 1H), 2.03-2.12 (m, 1H), 2.67-2.70 (m, 1H),2.81-2.02 (m, 2H), 3.06-3.15 (m, 1H), 3.30-3.37 (m, 4H), 3.58-3.63 (m,1H), 4.20 (dd, J=3.4, 14.2 Hz, 1H), 4.50-4.59 (m, 1H), 4.62-4.65 (m,3H), 5.00-5.03 (m, 1H), 6.75-6.81 (m, 2H), 7.31-7.37 (m, 1H), 8.27 (s,1H), 10.46 (s, 1H), 12.54 (s, 1H); ES⁺ MS: 477 (M+1).

Example Z-49racemic-(3aS,5aS,13aS)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-5-(2-methylpropyl)-10,12-dioxo-2,3,3a,4,5,5a,8,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) racemic-(1S,2S)-2-{([(2-Methylpropyl)amino]methyl}cyclopentanaminehydrochloride.

In a manner similar to example Z-18a-c, fromracemic-(1R,2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)cyclopentanecarboxylicacid (255 mg, 1.11 mmol) was prepared racemic-1,1-dimethylethyl[(1S,2S)-2-(aminomethyl)cyclopentyl]carbamate (153 mg, 64% over 3 steps)as a white green residue. Reductive amination with isobutyraldehydefollowed by deprotection as described in Z-38 steps c and drespectively, gaveracemic-(1S,2S)-2-{[((2-methylpropyl)amino]methyl}cyclopentanaminehydrochloride (105 mg, 39% over 5 steps from amino acid). ¹H NMR(methanol-d₄/CDCl₃) 8.90 (br s, <1H), 8.64 (br s, <1H), 8.28 (m, 1H),3.97 (br s, 1H), 3.37 (m, 1H), 2.83-2.69 (m, 3H), 2.18-1.69 (m, 7H),0.096 (m, 6H).

b)racemic-(3aS,5aS,13aS)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-5-(2-methylpropyl)-10,12-dioxo-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.In a manner similar to that described in example Z-35, fromracemic-(1S,2S)-2-{[(2-methylpropyl)amino]methyl}cyclopentanaminehydrochloride 105 mg, 0.434 mmol) and 16a (56 mg, 0.119 mmol) waspreparedracemic-(3aS,5aS,13aS)—N-[(2,4-difluorophenyl)methyl]-5-(2-methylpropyl)-10,12-dioxol-11-[(phenylmethyl)oxy]-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(62 mg, 74%). This material was deprotected in a second step similar tothe procedure described in example Z-37.

Thus, fromracemic-(3aS,5aS,13aS)—N-[(2,4-difluorophenyl)methyl]-5-(2-methylpropyl)10,12-dioxo-11-[(phenylmethyl)oxy]-2,3,3a,4,5,5a,6,10,12,13a-decahydro-1H-cyclopenta[e]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(48 mg, 0.081 mmol) and 10% Pd/C (catalytic amount), the title compoundwas prepared as a white solid after purification by HPLC (80 mg, 75%).¹H NMR (CDCl₃) 12.69 (s, 1H), 10.42 (s, 1H), 828 (s, 1H), 7.34 (m, 1H),6.79 (m, 2H), 4.83 (s, 1H), 4.68-4.58 (m, 3H), 4.29 (m, 1H), 4.14 (m,1H), 2.01 (m, 1H), 2.46-2.82 (m, 3H), 2.16-2.09 (m, 2H), 1.85-1.61 (m,5H), 1.39 (m, 1H), 0.88 (m, 6H); ES⁺ MS: 501 (M+1).

Example Z-50(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (40 mg, 0.09 mmol) and(2R)-2-amino-1-butanol (0.02 mL, 0.21 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(3R,11aS)—N-[(2,4-difluorophenyl)methyl)-3-ethyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro-1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(40 mg, 93%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(8R,11aS)—N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(30 mg, 91%) as a white solid. ¹H NMR (CDCl₃) δ 11.49 (br, 1H), 10.28(m, 1H), 8.35 (s, 1H), 7.34 (m, 1H), 6.70 (m, 2), 5.30 (m, 1H), 4.62 (m,2H), 4.45-4.32 (m, 3H), 3.93-3.86 (m, 2H), 2.11 (m, 1H), 1.65 (m, 1H),0.98 (t, J=7.6 Hz, 3H); ES⁺ MS: 420 (M+1).

Example Z-51racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide

a) racemic-1,1-Dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate. Analternative procedure from the one given in example Z-38b follows: To asolution of Dess-Martin Periodane (564 mg, 1.33 mmol) in dichloromethanewas added racemic-1,1-dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclohexyl]carbamate (305 mg, 1.33 mmol, seeexample Z-38a) dropwise as a solution in dichloromethane. The reactionwas stirred 1 hour at ambient temperature until judged complete by TLC(1:1 hexanes: ethyl acetate KMnO₄ stain). The reaction was quenched withaqueous sodium bicarbonate and sodium thiosulfate solutions, extractedwith dichloromethane, and the combined organics were dried over sodiumsulfate. Silica gel chromatography (0-50% ethyl acetate/hexanes gradientelution) gave racemic-1,1-dimethylethyl[(1S,2R)-2-formylcyclohexyl]carbamate (280, 93%). See example Z-88b forNMR data.

b)racemic-{[(1S,2S)-2Aminocyclohexyl]methyl}[2-(4-morpholinyl)ethyl]aminohydrochloride. In a manner similar to that described in example Z-38c-dfrom racemic-1,1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (78mg, 0.844 mmol, prepared using the procedure from example Z-38b) and[2-(4-morpholinyl)ethyl]amine (67 mg, 0.515 mmol) was preparedracemic-{[(1S,2S)-2-aminocyclohexyl]methyl}[2-(4-morpholinyl)ethyl]aminehydrochloride (95 mg, 78% over 2 steps) as a white solid. ¹H NMR(methanol-d₄/CDCl₃) 8.18 (br s, 1H), 8.84-8.498 (m, 11H), 3.19-3.119 (m,5H), 2.42 (m, 1H), 2.11 (br s, 2H), 1.87-1.17 (m, 10H).

c)racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.In a manner similar to that described in example Z-35, fromracemic-{[(1S,2S)-2-aminocyclohexyl]methyl}[2-(4-morpholinyl)ethyl]aminehydrochloride (95 mg, 0.272 mmol) and 16a (45 mg, 0.0957 mmol) waspreparedracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(27 mg, 43%). This material was deprotected in a second step similar tothe procedure described in example Z-87. Fromracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-[2-(4-morpholinyl)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (27 mg, 0.0408 mmol) and10% Pd/C (1 mg) the title compound was prepared as a white solid afterpurification by HPLC. ¹H NMR (CDCl₃) 12.80 (br s, <1H), 10.41 (br s,1H), 8.29 (s, 1H), 7.34 (m, 2H), 6.78 (m, 2H), 4.76 (m, 1H), 4.62-4.54(m, 3H), 4.29 (m, 2H), 3.65 (m, 4H), 8.01 (m, 1H), 2.76 (m, 2H),2.58-2.42 (m, 7H), 2.21 (m, 1H), 1.89-1.28 (m, 3H); ES⁺ MS: 572 (M+1).

Example Z-52racemic-(3aR,5aR,13aS)—N-[(2,4-Difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,8,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide

a) racemic-1,1-Dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclopentyl]carbamate.racemic-(1R,2S)-2-({[(1,1-Dimethylethyl)oxy]carbonyl}amino)cyclopentanecarboxylicacid (22 mg, 0.096 mmol) was dissolved in tetrahydrofuran and placed inan ice-water bath. Triethylamine was added, followed by the slowaddition of methyl chloroformate. The reaction was stirred ten minutesin the ice-bath and sodium borohydride was added. Methanol was thenadded slowly and stirring was continued for two hours while the ice-bathexpired. 1 M Potassium hydrogen sulfate was added, the reaction waspartially concentrated, and product was extracted with dichloromethane.The combined organics were washed with sodium bicarbonate, brine, anddried over sodium sulfate. Removal of solvents under reduced pressureafforded racemic-1,1dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclopentyl]carbamate (25 mg, >100%), ¹H NMR(CDCl₃) 4.50 (br s, 1H), 4.06 (m, 1H), 3.54 (m. 1H), 8.87 (m, 1H), 2.09(m, 1H), 1.96 (m, 1H), 1.64 (m, 3H), 1.52 (m, 1H), 1.43 (a, 9H), 1.11(m, 2H).

b) racemic-[(1R,2S)-2-Aminocyclopentyl]methanol hydrochloride. In amanner similar to that described in example, fromracemic-1,1-dimethylethyl[(1S,2R)-2-(hydroxymethyl)cyclopentyl]carbamate and 4 N HCl was preparedracemic-[(1R,2S)-2-aminocyclopentyl]methanol hydrochloride (20 mg,quantitative). ¹H NMR (methanol-d4-CDCl₃) 7.76 (br s, <1H), 3.73 (m,1H), 3.61-3.28 (m, 3H), 2.27 (br s, 1H), 2.01 (m, 2.01 (m, 1H),1.74-1.70 (m, 2H), 1.56-1.42 (m, 2H), 1.16 (br s, 1H), 1.05 (br s, 1H).

c) racemic-(3aR,13aS)—N-[(2,4-Difluorophenyl)methyl]-11hydroxy-10,12-dioxo-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide.In a manner similar to that described in example Z-35, fromracemic-[(1R,2S)-2-aminocyclopentyl]methanol hydrochloride (20 mg, 0.132mmol) and 16a (24 mg, 0.051 mmol) was preparedracemic-(3aR,13aS)—N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)oxy]-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide(7 mg, 26%) as a white solid. This material was deprotected in a secondstep similar to the procedure described in example Z-87. Thus, fromracemic-(3aR,13aS)—N-[(2,4-difluorophenyl)methyl]-10,12-dioxo-11-[(phenylmethyl)oxy]-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide(7 mg, 0.012 mmol) and 10% Pd/C (1 mg),racemic-(3aR,13aS)—N-[(2,4-difluorophenyl)methyl]-11-hydroxy-10,12-dioxo-1,2,3,3a,4,5a,6,10,12,13a-decahydrocyclopenta[d]pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-carboxamide(4 mg, 72%) white solid. ¹H NMR (CDCl₃) 12.20 (br s, 1H), 10.37 (br s,1H), 8.31 (s, 1H), 7.35 (m, 1H), 6.80 (m, 2H), 5.16 (m, 1H), 4.17 (m,1H), 4.64 (m, 2H), 4.28 (m, 1H), 4.09 (m, 1H), 3.97 (m, 1H), 3.45 (m,1H), 2.40-2.20 (m, 2H), 1.89-1.58 (m, 4H), 0.936-0.840 (m, 1H); ES⁺ MS:446 (M+1).

Example Z-53racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-methyl-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide

a) racemic-{[(1S,2S)-2-Aminocyclohexyl]methyl}methylamine hydrochloride.In a manner similar to that described in example Z-38c-d fromracemic-1,1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (0.410mmol) and methyl amine (0.5 mL of a 2 M tetrahydrofuran solution) wasprepared racemic-{[(1S,2S)-2-aminocyclohexyl]methyl}methylaminehydrochloride in two steps as a white solid (46 ing, 03% 2 steps). ¹HNMR (methanol-d4/CDCl₃) 9.05 (br s, <1H), 8.72 (br s, <1H), 8.24 (br s,1H), 3.34 (m, 1H), 3.20 (m, 1H), 2.85 (br s, 1H), 2.66 (br s, 4H), 2.38(br s, 1H), 2.07-1.88 (m, 2H), 1.67-1.14 (m, 6H).

b)racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6methyl-11,13dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.In a manner similar to that described in example Z-35, fromracemic-{[(1S,2S) 2-aminocyclohexyl]methyl}methylamine hydrochloride (46mg, 0.215 mmol) and 16a (35 mg, 0.0744 mmol) was preparedracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(17 mg, 41%) as a white solid. This material was deprotected in s secondstep similar to the procedure described in example Z-37.

Thus, fromracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-methyl-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(17 mg, 0.0302 mmol) and 10% Pd/C (1 mg) was prepared the title compoundas a white solid (9 mg, 64%). ¹H NMR (CDCl₃) 10.44 (m, 1H), 8.29 (s,1H), 7.34 (m, 1H), 6.79 (m, 2H), 4.78 (m, 1H), 4.62 (br s, 2H), 4.20 (brs, 2H), 3.41 (s, 1H), 2.92 (m, 1H), 2.66 (m, 1H), 2.35-2.25 (m, 4H),1.90-1.74 (m, 2H), 1.67-1.24 (m, 6H); ES⁺ MS: 473 (M+1).

Example Z-54racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12hydroxy-6-[2-(methyloxy)ethyl]-11,13dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide

a) racemic-{[(1S,2S)-2-Aminocyclohexyl]methyl}[2-(methyloxy)ethyl]aminehydrochloride.

In a manner similar to that described in example Z-38c-d fromracemic-1,1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (93 mg,0.410 mmol) and [2-(methyloxy)ethyl]amine (0.05 mL, 0.615 mmol) wasprepared in two stepsracemic-{[(1S,2S)-2-aminocyclohexyl]methyl}[2-(methyloxy)ethyl]aminehydrochloride (63 mg, 60% 2 steps) as a white solid. ¹H NMR(methanol-d₄/CDCl₃) 9.02 (br s, <1H), 8.78 (br s, <1H), 8.29 (br s, 1H),3.69 (br s, 2H), 3.46)s, 3H), 3.36-3.18 (m, 4H), 2.97 (br s, 1H), 2.46(br s, 1H), 1.86-1.40 (m, 3H).

b) racemic-4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-[2(methyloxy)ethyl]-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.In a manner similar to that described in example Z-35, fromracemic-{[(1S,2S)-2-aminocyclohexyl]methyl}[2-(methyloxy)ethyl]aminehydrochloride (63 mg. 0.244 mmol) and 16a (40 mg, 0.0851 mmol) waspreparedracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl)]-6-[2-(methyloxy)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(44 mg, 81%) as a white solid. This material was deprotected in a secondstep similar to the procedure described in example Z-37. Thus, fromracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-[2-(methyloxy)ethyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(44 mg, 0.0726 mmol) and 10% Pd/C (1 mg) the title compound was preparedas a white solid (37 mg, quantitative). ¹H NMR (CDCl₃) 12.60 (br s, 1H),10.47 (m, 1H), 8.28 (s, 1H), 7.34 (m, 1H), 6.70 (m, 2H), 4.81 (m, 1H),4.64 (m, 3H), 4.51 (m, 1H), 4.26 (m, 1H), 8.63 (m, 1H), 3.31 (a, 3H),3.10 Cm, 1H), 2.86 (m, 1H), 2.67 (2m, 2H), 2.21 (m, 1H), 1.01-1.78 (m,2H), 1.67-1.52 (m, 4H), 1.46-1.24 (m, 3H); ES⁺ MS: 517 (M+1).

Example Z-55racemic-(4aS,6aS,14aS)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide

a)racemic-N-[2-({[(1S,2S)-2-Aminocyclohexyl]methyl}amino)ethyl]acetamidehydrochloride. In a manner similar to that described in example Z-38c-dfrom racemic-1,1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate (98mg, 0.41 mmol) and N-(2-aminoethyl)acetamide (63 mg, 0.615 mmol),racemic-N-[(2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethyl]acetamidehydrochloride was prepared in two steps as a white solid (82 mg), 71% 2steps). ¹H NMR (methanol-d4/CDCl₃) 8.86 (br s, 1H), 8.29 (br s, 1H),3.62-3.51 (m, 3H), 3.40-3.28 (m, 4H), 3.22-2.93 (m, 3H), 2.47 (m, 1H),2.08-2.06 (m, 4H), 1.83-1.75 (m, 2H), 1.56-1.44 (m, 3H), 1.28 (m, 1H).

b)racemic-4aS,6aS,14aS)-6-[2-(Acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.In a manner similar to that described in example Z-35, fromracemic-N-[2-({([(1S,2S)-2-aminocyclohexyl]methyl}amino)ethyl]acetamidehydrochloride (32 mg, 0.849 mmol) and 16a (50 mg, 0.106 mmol) wasprepared the title compound (24 mg, 86%). This material was deprotectedin a second step similar to the procedure described in example Z-37.Thus, from racemic(4aS,6aS,14aS)-6-[2-(acetylamino)ethyl]-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(24 mg, 0.0379 mmol) and 10% Pd/C (1 mg) was prepared the title compoundas a white solid after purification by HPLC. ¹H NMR (CDCl₃) 12.50 (s,1H), 10.44 (s, 1H), 8.35 (s, 1H), 7.32 (m, 1H), 6.79 (m, 2H), 5.86 (s,1H), 4.78 (m, 1H), 4.61*4.50 (m, 3H), 4.30 (m, 1H), 8.35 (m, 1H), 3.18(m, 1H), 2.96 (m, 1H), 2.76 (m, 2H), 2.48 (m, 1H), 2.19 (m, 1H),1.89-1.28 (m, 12H): ES⁺ MS: 544 (M+1).

Example Z-56(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (40 mg, 0.09 mmol) and(2S)-2-amino-1-butanol (0.1 mL) wore reacted in dichloromethane (2 mL)with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-ethyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(89 mg, 90%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-ethyl-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(87 mg, 990%) as a tinted white solid. ¹H NMR (CDCl₃) δ 11.47 (br, 1H),10.26 (m, 1H), 8.35 (s, 1H), 7.32 (m, 1H), 6.77 (m, 2), 5.29 (m, 1H),4.60 (m, 2H), 4.47-4.32 (m, 3H), 3.93-3.85 (m, 2H), 2.08 (m, 1H), 1.68(m, 1H), 0.95 (t, J=7.6 Hz, 3H); ES⁺ MS: 420 (M+1).

Example Z-57(3S,11aR)-3-Butyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (40 mg, 0.09 mmol) and(2S)-2-amino-1-hexanol (100 mg) were reacted in dichloromethane (2 mL)with acetic acid to give(3S,11aR)-3-butyl-[(2,4-difluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(43 mg, 94%). This material was hydrogenated in a second step asdescribed in example Z-2 to give(3S,11aR)-3-butyl-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,8,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(33 mg, 92%) as a tinted white solid. ¹H NMR (CDCl₃) δ 11.48 (br, 1H),10.27 (br, 1H), 8.36 (br, 1H), 7.31 (m, 1H), 6.77 (m, 2), 5.28 (m, 1H),4.59-4.36 (m, 5H), 3.83 (m, 2H), 2.08 (m, 1H), 1.58 (m, 1H), 1.89-1.23(m, 4H), 9.90 (t, J=6.8 Hz, 3H); ES⁺ MS: 448 (M+1).

Example Z-58(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-[(4-hydroxyphenyl)methyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (40 mg, 0.09 mmol) and4-[(2S)-2-amino-3-hydroxypropyl]phenol (43 mg, 0.21 mmol) were reactedin dichloromethane (2 mL) with acetic acid to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3[(4-hydroxyphenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,8,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(10 mg, 20%). This material was hydrogenated in a second step asdescribed in example Z-2 and purified via preparative HPLC to give(3S,11aR)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-[(4hydroxyphenyl)methyl]-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide(7 mg, 63%) as a white solid. ¹H NMR (CD₃OD) δ 10.43 (m, 1H), 8.34 (s,1H), 7.33 (m, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.82 (m, 2H), 6.71 (d, J=8.4H-z, 2H), 5.05 (m, 1H), 4.67-4.57 (m, 4H), 4.21 (dd, J=8.8, 7.2 Hz, 1H),3.94 (dd, J=8.8, 6.4 Hz, 1H), 3.21 (dd, J=13.2, 3.2 Hz, 1H), 2.90 (dd,J=13.6, 8.8 Hz, 1H); ES⁺ MS: 498 (M+1).

Example Z-59(4S,12aS)-1-Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-3-Aminobutyl]cyclobutylamine dihydrochloride was prepared in asimilar manner as described in example Z-47. ¹H NMR (400 MHz,CDCl₃/CD₃OD) δ 1.23 (d, J=6.4 Hz, 3H), 1.60-2.26 (m, 3H), 2.83 (m, 2H),8.31-3.33 (m, 1H), 8.55 (m, 1H), 8.08 (br, <1H), 9.07 (br, <1H).

b) (4S,12aS)-1-Cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (80 mg, 0.17 mmol) and free based[(3S)-3-aminobutyl]cyclobutylamine (96 mg, 0.68 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(4S,12aS)-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(68 mg, 70%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)-1-cyclobutyl-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(57 mg, 100%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 1.31 (d,J=6.8 Hz, 3H), 1.46-1.70 (m, 4H), 1.91-2.12 (m, 4H), 2.52 (m, 1H),2.00-2.93 (m, 1H), 3.06 (m, 1H), 4.16-4.29 (m, 3H), 4.57-4.66 (m, 2H),4.09-5.05 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 1H), 8.20 (s, 1H),10.44 (s, 1H), 12.53 (s, 1H); ES⁺ MS: 473 (M+1).

Example Z-60(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-3-Aminobutyl]tetrahydro-2H-thiopyran-4-ylamine dihydrochloridewas prepared in a similar manner as described in example Z-47. ¹H NMR(400 MHz, CDCl₃/CD₃OD) δ 1.21 (d, J=6.4 Hz, 3H), 1.65-1.75 (m, 2H),1.90-2.10 (m, 2H), 2.35 (m, 2H), 2.56-2.61 (m, 4H), 2.92-2.98 (m, 3H),3.27-3.31 (m, 1H), 8.05 (br, <1H), 8.90 (br, <1H).

b)(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidino-9carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (80 mg, 0.17 mmol) and free based[(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine (108 mg, 0.58 mmol)were reacted in dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-[(phenylethyl)oxy]-1-(tetrahydro-2-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(58 mg, 54%) as a film. This material was debenzylated in a second stepto in a manner similar to Z-26 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(56 mg, >100%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.30 (d,J=6.8 Hz, 3H), 1.54-1.58 (m, 1H), 1.72-1.82 (m, 3H), 1.97-2.11 (m, 2H),2.60-2.76 (5H), 2.86 (m, 2H), 4.17-4.80 (m, 2H), 4.62-4.66 (m, 3H),4.02-4.6 (m, 1H), 6.75-6.82 (m, 2H), 7.32-7.38 (m, 1H), 8.31 (s, 1H),10.46 (s, 1H), 12.48 (s, 1H); ES⁺ MS: 519 (M+1).

Example Z-61(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-3-Amino-5-methylhexyl](2-methylpropyl)amine dihydrochloride wasprepared in a similar manner as described in example Z-32. ¹H NMR (400MHz, CDCl₃/CD₃OD) δ 0.87 (d, J=6.4 Hz, 6H), 0.97 (d, J=6.8 Hz, 6H),1.34-1.41 (m, 1H), 1.45-1.52 (m, 1H), 1.58-1.66 (m, 1H), 2.01-2.13 (m,2H), 2.72-2.73 (m, 2H), 3.03-3.00 (m, 2H), 3.20 (m, 2H), 8.07 (br, <1H),8.71 (br, <1H).

b)(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (80 mg, 0.17 mmol) and free based[(3S)-8-amino-5-methylhexyl](2-methylpropyl)amine (117 mg, 0.68 mmol)were reacted in dichloromethane (2 mL) with acetic acid to give (4,12aS)—N-[(2,4-difluorophenyl)methyl]-1,4-bis(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(68 mg, 66%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(56 mg, 97%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 0.74 (d,J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.83 (m,5H), 2.03-2.12 (m, 2H), 2.21-2.28 (m, 1H), 2.77 (m, 1H), 2.00-2.093 (m,1H), 4.19-4.40 (m, 3H), 4.59-4.70 (m, 2H), 4.96-4.97 (m, 1H), 6.77-6.83(m, 2H), 7.33-7.39 (m, 1H), 8.28 (s, 1H), 10.47 (s, 1H), 12.59 (br, 1H);ES⁺ MS: 517 (M+1).

Example Z-62racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-hydroxyethyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide

a) racemic-2-({[(1S,2S)-2-Aminocyclohexyl]methyl}amino) ethanolhydrochloride. In a manner similar to that described in example Z-55a,from racemic-1,1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate(112 mg, 0.497 mmol) and 2-aminoethanol (0.04 mLm 0.746 mmol) wasprepared racemic 2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethanolbis-hydrochloride in two steps (102 mg, 84% over 2 steps). ¹H NMR(methanol-d4/CDCl3) 8.81-8.40 (m, <2H), 8.16 (br s, 1H), 4.02-3.93 (m,2H), 3.80 (br s, 2H), 3.53 (m, 1H), 3.36-2.93 (m, 6H), 2.41 (br s, 1H),2.05 (m, 1H), 1.75-1.41 (m, 4H).

b)racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-6-(2-hydroxyethyl)-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.In a manner similar to that described in example Z-35, from 16a (45 mg,0.0957 mmol) andracemic-2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethanolhydrochloride (102 mg, 0.418 mmol) was preparedracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10carboxamide(7 mg, 12%) as a white solid after silica gel chromatography (1.12%methanol/dichloromethane gradient elution). This material wasdeprotected in a second step similar to the procedure described inexample Z-37. Thus, fromracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,8,8a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5)pyrazino[1,2-a]quinazoline-10-carboxamide(7 mg, 0.0118 mmol) the title compound was prepared after purificationby HPLC (3 mg, 50%). ¹H NMR (CDCl₃) 12.57 (br s, 1H), 10.45 (m, 1H),8.20 (s, 1H), 7.34 (m, 1H), 6.78 (m, 2H), 4.80 (m, 1H), 4.71 (s, 1H),4.62 (m, 2H), 4.44 (m, 1H), 4.33 (m, 1H), 3.75 (m, 1H), 3.62-3.20 (m,3H), 3.13 (m, 1H), 2.74-2.71 (m, 2H), 2.24 (m, 1H), 1.90-137 (m, 12H),1.27-1.23 (m, 3H) 1.12 (m, 1H); ES⁺ MS: 503 (M+1).

Example Z-63racemic-(4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide

a) racemic-(1S,2S) 2-[(Cyclopropylamino)methyl]cyclohexanaminehydrochloride. In a manner similar to that described in example Z-55a,from racemic-1,1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate(112 mg, 0.497 mmol) and cyclopropylamine (0.05 mL, 0.746 mmol) wasprepared racemic-(1S,2S)-2-[(cyclopropylamino)methyl]cyclohexan aminebis hydrochloride salt in two steps (102 mg, 86% over 2 steps). Thismaterial was used without further purification. ¹H NMR(methanol-d₄/CDCl₃) 8.31 (br s, 1H), 3.75 (br s, 1H), 3.54 (m, 1H), 2.96(m, 1H), 2.71 (m, 1H), 2.27 (m, 1H), 1.94 (m, 1H), 1.76-1.15 (m, 3H),0.88-0.78 (m, 3H).

b)racemic-(4aS,6aS,14aS)-6-Cyclopropyl-N-[(2,4-difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide.In a manner similar to that described in example Z-35, from 16a (45 mg,0.0957 mmol) andracemic-(1S,2S)-2-[(cyclopropylamino)methyl]cyclohexanaminehydrochloride (102 mg, 0.425 mmol) was prepared racemic4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamideas a white solid after silica gel chromatography (1-12%methanol/dichloromethane gradient elution). This material wasdeprotected in a second step similar to the procedure described inexample Z-87. Thus, fromracemic-(4aS,6aS,14aS)-6-cyclopropyl-N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(56 mg, 0.0949 mmol) the title compound was prepared as a white solid(41 mg, 81%). ¹H NMR (CDCl₃) 12.10 (br s, <1H), 10.45 (m, 1H), 8.27 (s,1H), 7.33 (m, 1H), 6.88 (m, 2H), 4.77 (m, 1H), 4.61-4.40 (m, 4H), 4.33(m, 1H), 2.94 (m, 1H), 2.79 (m, 1H), 2.17 (m, 1H), 1.86-0.86 (m, 10H),0.658 (m, 1H), 0.499-0.32 (m, 2H); ES⁺ MS: 499 (M+1).

Example Z-64racemic-(4aS,6aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-6-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamideformic acid salt

a)racemic-(1S,2S)-2-({[2-(1-Pyrrolidinyl)ethyl}amino)methyl)cyclohexanaminehydrochloride. In a manner similar to that described in example Z-55a,from racemic-1,1-dimethylethyl [(1S,2R)-2-formylcyclohexyl]carbamate(112 mg, 0.407 mmol) and 2-(1-pyrrolidinyl)ethanamine (0.09 mL, 0.746mmol) was preparedracemic-(1S,2S)-2-({[2-(1-pyrrolidinyl)ethyl]amino}methyl)cyclohexanamine(88 mg, 60% 2 steps) as the bis hydrochloride salt in two steps as awhite solid. ¹H NMR (methanol-d₄/CDCl₃) 9.68 (br s, <1H), 9.24 (br s,<1H), 8.25 (br s, 1H), 3.75-3.04 (m, 11H), 2.87 (br s, 1H), 2.06-1.20(m, 12H).

b)racemic-(4aS,6aS,14aS)—N-(2,4-Difluorophenyl)methyl]-12-hydroxy-11,13-dioxo-6-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2a]quinazoline-10-carboxamideformic acid salt.

In a manner similar to that described in example Z-85, from 16a (30 mg,0.0688 mmol) andracemic-(1S,2S)-2-({[2-(1-pyrrolidinyl)ethyl]amino}methyl)cyclohexanaminehydrochloride (88 mg, 0.296 mmol) was preparedracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-6-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamideas a white solid (31 mg, 76%) after silica gel chromatography (I-12%methanol/dichloromethane gradient elution), This material wasdeprotected in a second step similar to the procedure described inexample Z-87. Thus, fromracemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-11,13-dioxo-1,2-[(phenylmethyl)oxy]-6-[2-(1-pyrrolidinyl)ethyl]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide(31 mg, 0.048 mmol) the title compound was prepared as a yellow solidafter purification by HPLC (18 mg, 66%). ¹H NMR (CDCl₃) 10.39 (br s,1H), 8.56 (br s, 1H), 8.390 (br s, 1H), 7.34 (m, 1H), 6.78 (m, 2H),4.76-4.40 (m, 6H), 3.26-2.89 (m, 7H), 2.78 (m, 1H), 2.15 (m, 1H),2.02-1.18 (m, 14H); ES⁺ MS: 556 (M+1).

Example Z-65

(4aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-9-hydroxy-8,10-dioxo-2,3,4,4a,5,6,8,10,14,14a-decahydro1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide

a) {2-[(2S)-2-Piperidinyl]ethyl}amine. This compound was prepared in asimilar manner as its enantiomer described in example Z-42a.

b) (4aS,14aS)—N-[(2,4-Difluorophenyl)methyl]-9hydroxy-8,10-dioxo-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide.In a manner similar to that described in example Z-35, from{2-[(2S)-2-piperidinyl]ethyl}amine (28 mg, 0.218 mmol) and 16a (30 mg,0.0638 mmol) was prepared(4aS,14aS)—N-[(2,4-difluorophenyl)methyl]-8,10-dioxo-9-[(phenylmethyl)oxy]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide(29 mg, 82%). This material was deprotected in a second step similar tothat described in example Z-37 to give the title compound as a whitesolid (26 mg, quantitative). ¹H NMR (CDCl₃) δ 12.44 (br s, 1H), 10.48(s, 1H), 8.26 (s, 1H), 7.35 (m, 1H), 6.80 (m, 2H), 4.68-4.57 (m, 2H),4.38 (m, 1H), 4.20 (m, 1H), 3.93 (s, 1H), 3.63-3.39 (m, 2H), 2.91 (m,2H), 2.29 (br s, 1H), 2.02 (m, 1H), 1.69-1.45 (m, 4H), 1.80-1.24 (m,2H), 1.12 (br s, 1H); ES⁺ MS: 459 (M+1).

Example Z-66(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-3-Aminobutyl][2-(methyloxy)ethyl]amine bis hydrochloride. In amanner similar to that described in example 2.47, from 1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (76 mg, 0.406 mmol) and2-(methyloxy)ethyl]amine (0.05 mL, 0.609 mmol) was prepared[(3S)-3-aminobutyl][2-(methyloxy)ethyl]amine as the bis hydrochloridesalt in two stops (19 mg, quantitative). ¹H NMR (methanol-d₄/CDCl₃) δ9.02 (<1H), 8.24 (<1H), 3.68 (br s, 2H), 3.490 (br s, 1H), 3.34 (br s,4H), 3.15 (br s, 4H), 2.26-2.11 (m, 2H), 1.35 (br s, 3H).

b)(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7hydroxy-4-methy-1-[2-(methyloxy)ethyl]-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido-[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.In a manner similar to that described in example Z-36, from 16 (15 mg,0.034 mmol) and [(3S)-3-Aminobutyl][2-(methyloxy)ethyl]amine bishydrochloride (19 mg, 0.087 mmol),(4S,12aS)—N-[(4fluorophenyl)methyl]-4-methyl-1-[2-(methyloxy)ethyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamidewas prepared as a white solid after silica gel chromatography (I-12%methanol/dichloromethane). This material was deprotected in a secondstep similar to that described in example Z-37 to give the titlecompound as a yellow solid (9 mg, 60%, 2 steps). ¹H NMR (CDCl₃) δ 12.56(s, 1H), 10.51 (m, 1H), 8.29 (s, 1H), 7.32 (m, 2H), 6.98 (m, 2H), 5.08(m, 1H), 4.65-4.59 (m, 2H), 4.53 (m, 1H), 4.21 (m, 1H), 3.61-3.40 (m,2H), 3.34-3.13 (m, 3H), 3.08 (m, 1H), 2.04-2.84 (m, 2H), 2.68 (m, 1H),2.07 (m, 1H), 1.50 (m, 1H), 1.35 (d, J=7.2 Hz, 3H), 1.14 (m, 1H); ES⁺MS: 459 (M+1).

Example Z-67(4S,12aS)-1-Cyclobutyl-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(8S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride. In a mannersimilar to that described in example Z-47, from 1,1-dimethylethyl[(1S)-1-methyl-3-oxopropyl]carbamate (76 mg, 0.406 mmol) andcyclobutylamine (0.05 mL, 0.609 mmol) was prepared[(3S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride in two steps (23mg, 27%). ¹H NMR (methanol-d₄/CDCl₃) δ 8.86 (a, <1H), 7.97 (a, <1H),3.46 (m, 1H), 3.23 (m, 1H), 2.74 (m, 2H), 2.14-2.08 (m, 4H), 1.94-1.62(m, 5H), 1.13 (d, J=6 Hz, 1H).

b)(4S,12aS)-1-Cyclobutyl-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.In a similar manner to that described in example Z-35a, from 16 (18 mg,0.39 mmol) and [(3S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride (23mg, 0.107 mmol),(4S,12aS)-1-cyclobutyl-N-[(4-fluorophenyl)methyl]-4methyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamidewas prepared as a white solid. This material was deprotected in a secondstep similar to that described in example Z-37 to give the titlecompound as a white solid after purification by HPLC (4.5 mg, 25% 2steps). ¹H NMR (CDCl₃) δ 12.54 (s, 1H), 10.48 (s, 1H), 8.20 (s, 1H),7.31 (m, 2H), 6.08 (m, 2H), 5.02 (m, 1H), 4.61-4.57 (m, 2H), 4.26-4.14(m, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.49 (m, 1H), 2.12 (m, 1H),2.0561.87 (m, 3H), 1.84-1.61 (m, 3H), 1.46 (m, 1H), 1.32 (m, 3H); ES⁺MS: 455 (M+1).

Example Z-68(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-3-Aminobutyl](2-methylpropyl)amine bis-hydrochloride. In amanner similar to that described in example Z-47, this compound wasprepared from 1,1-dimethylethyl [(1S)-1-methyl-3-oxopropyl]carbamate (76mg, 0.406 mmol) and (2-methylpropyl)amine (0.06 mL, 0.609 mmol) in twosteps as the bis-hydrochloride salt (22 mg, 25%). ¹H NMR(methanol-d₄/CDCl₃) δ 3.25 (br s, 1H), 2.91 (br s, 2H), 2.64 (m, 2H),2.02-1.98 (m, 3H), 1.17 (m, 3H), 0.88 (m, 6H).

b)(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.In a similar manner to that described in example Z-35, from 16 (16 mg,0.035 mmol) and [(3S)-3-Aminobutyl](2-methylpropyl)aminebis-hydrochloride (20 mg, 0.0925 mmol),(4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamidewas prepared as a white solid. This material was deprotected in a secondstep similar to that described in example Z-37 to give the titlecompound as a tan solid (13 mg, 68% 2 steps). ¹H NMR (CDCl₃) δ 12.57 (s,1H), 10.46 (s, 1H), 8.27 (s, 1H), 7.32 (m, 2H), 6.99 (m, 2H), 4.98 (min,1H), 4.6384.54 (m, 2H), 4.45 (m, 1H), 4.26-4.16 (m, 2H), 2.91 (m, 1H),2.77 (m, 1H), 2.24 (m, 1H), 2.14-2.03 (m, 2H), 1.68 (m, 1H), 1.48 (m,1H), 1.33 (m, 3H), 1.09 (m, 1H), 0.850 (m, 3H), 0.789 (m, 8H); ES⁺ MS:457 (M+1).

Example Z-69(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,4,8,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(3S)-8-Aminobutyl]methylamine bis-hydrochloride. In a manner similarto that described in example Z-47, this compound was prepared from1,1-dimethylethyl [(1S)-1-methyl-3-oxopropyl]carbamate (76 mg, 0.409mmol) and excess methylamine (2 M in tetrahydrofuran) in two steps asthe bis hydrochloride salt (17% 2 steps). ¹H NMR (methanol-d₄/CDCl₃) δ3.16 (m, 1H), 3.08 (s, 2H), 2.83 (m, 2H), 2.45 (s, 3H), 1.88 (m, 1H),1.75 (m, 1H), 1.09 (m, 3H).

b)(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2a]pyrimidine-9-carboxamide.In a similar manner to that described in example Z-35, from 16 (18 mg,0.0398 mmol) and [(3S)-3-aminobutyl]methylamine bis-hydrochloride (10mg, 0.109 mmol,(4S,12aS)—N-[(4-fluorophenyl)methyl]-1,4-dimethyl-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamidewas prepared as a white solid. This material was deprotected in a secondstep similar to that described in example Z-87 to give the titlecompound as a tan solid (7 mg, 44% 2 steps). ¹H NMR (CDCl₃) δ 12.53 (s,1H), 10.47 (s, 1H), 8.29 (s, 1H), 7.32 (m, 2H), 6.99 (m, 2H), 5.04 (1H),4.60 (m, 2H), 4.28 (s, 3H), 2.88-2.80 (m, 2H), 2.32 (s, 3H), 2.18 (m,1H), 1.48 (m, 1H), 1.34 (m, 3H); ES⁺ MS: 415 (M+1).

Example Z-70(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16 (25 mg, 0.055 mmol) and free based[(3S)-3-aminobutyl]tetrahydro-2H-thiopyran-4-ylamine (48 mg, 0.26 mmol)were reacted in dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-6,8-dioxo7-[(phenylmethyl)oxy]-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(16 mg, 49%) as a film. This material was debenzylated in a second stepin a manner similar to Z-26 to give(4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-1-(tetrahydro-2H-thiopyran-4-yl)-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(8 mg, 59%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 1.80 (d,J=7.2 Hz, 3H), 1.583-1.58 (m, 1H), 1.72-2.10 (m, 5H), 2.56-2.76 (m, 5H),2.84-2.87 (m, 2H), 4.18 (dd, J=2.8, 14.0 Hz, 1H), 4.26 (dd, J=3.4, 14.2Hz, 1H), 4.92-4.97 (m, 1H), 6.96-7.00 (m, 2H), 7.29-7.36 (m, 2H), 8.31(s, 1H), 10.48 (m, 1H), 12.48 (br, 1H); ES⁺ MS: 501 (M+1).

Example Z-71(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

a) [(34′3-Aminobutyl]methylamine dihydrochloride was prepared in asimilar manner as described in example Z-47. ¹H NMR (400 MHz, CDCl3) δ1.18 (d, J=6.8 Hz, 3H), 1.82-1.91 (m, 1H), 1.94-2.03 (m, 1H), 2.53 (s,3H), 2.89-2.93 (m, 2H), 3.22-3.30 (m, 1H), 8.02 (br, <1H), 8.81 (br,<1H).

b)(4S,12aS)—N-[(2,4-Difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide.The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16a (40 mg, 0.085 mmol) and free based[(3S)-3-aminobutyl]methylamine (24 mg, 0.28 mmol) were reacted indichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-1,4dimethyl-6,8dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(39 mg, 89%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(2,4-difluorophenyl)methyl]-7-hydroxy-1,4-dimethyl-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(32 mg, 97%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 1.33 (d,J=6.4 Hz, 3H), 1.46-1.50 (m, 1H), 2.12-2.14 (m, 1H), 2.32 (s, 3H), 2.83(m, 2H), 4.24 (m, 3H), 4.62 (m, 2H), 5.02 (m, 1H), 6.77-6.79 (m, 2H),7.33 (m, 1H), 8.30 (s, 1H), 10.43 (s, 1H), 12.50 (br, 1H); ES⁺ MS: 433(M+1).

Example Z-72(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-10-carboxamide

The title compound was made in two stops using a similar process to thatdescribed in example Z-2. 16 (27 mg, 0.060 mmol) and free based[(3S)-3-aminobutyl](1methylethyl)amine (67 mg, 0.51 mmol) were reactedin dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(1-methylethyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(18 mg, 56%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(1-methylethyl)-6,8dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(15 mg, >100%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 1.02 (d,J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H), 1.32 (d, J=6.8 Hz, 31H),1.54-1.58 (m, 1H), 1.04-2.03 (m, 1H), 2.71-2.76 (m, 1H), 2.82-2.88 (m,1H), 3.13-3.16 (m, 1H), 4.16-4.19 (m, 1H), 4.30-4.33 (m, 1H), 4.48 (m,1H), 4.55-4.65 (m, 2H), 4.07-5.00 (m, 1H), 6.97-7.01 (m, 2H), 7.30-7.34(m, 2H), 8.28 (s, 1H), 10.51 (m, 1H), 12.55 (s, 1H); ES⁺ MS: 443 (M+1).

Example Z-78(4S,12aS)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

The title compound was made in two steps using a similar process to thatdescribed in example Z-2. 16 (25 mg, 0.066 mmol) and free based[(3S)-3-amino-5-methylhexyl](2-methylpropyl)amine (21 mg, 0.11 mmol)were reacted in dichloromethane (2 mL) with acetic acid to give(4S,12aS)—N-[(4-fluorophenyl)methyl]-1,4-bis(2-methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(8 mg, 25%) as a film. This material was hydrogenated in a second stepas described in example Z-2 to give(4S,12aS)—N-[(4-fluorophenyl)methyl]-7-hydroxy1,4-bis(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide(5 mg, 78%) as an off-white solid. ¹H NMR (400 MHz, CDCl3) δ 0.74 (d,J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 0.97-1.00 (m, 6H), 1.37-1.66 (m,5H), 1.75-1.82 (m, 1), 2.05-2.00 (m, 2H), 2.21-2.26 (m, 1H), 2.72-2.70(m, 1H), 2.87-2.03 (m, 1H), 4.16-4.26 (m, 2H), 4.38 (m, 1H), 4.556-4.66(m, 2H), 4.93-4.99 (m, 1H), 6.97-7.02 (m, 2H), 7.31-7.34 (m, 2H), 8.27(s, 1H), 10.49 (m, 1H), 12.61 (s, 1H); ES⁺ MS: 409 (M+1).

Example ZZ-1 to ZZ-24

Examples in table below were Isolated as a mixture of diastereomersranging from 1:1 to >10:1 ratios of stereoisomers at the centerindicated as undefined. Characterization data reported herein consistsof observed mass spectral signals for molecular ions (M+1) of thecompounds using electrospray ionization methods in the positive modeusing LC/MS techniques well known in the field. Reported retention timesrefer to observed UV peaks confirmed by NMR methods for the examplesbelow using the following gradient on a phenomenex C18 reverse phaseHPLC column (150 mm×4.6 mm 5 micron). Solvent A=water w/ 0.1% formicacid, solvent B=acetonitrile w/ 0.1% formic acid. Gradient=10% B for 1min, gradient from 10% to 90% B from 1 to 9 min, ramping to 100% B at9.01 min and holding at 100% B for 2 min. In several cases thediastereomers were not separable by the standard HPLC conditionsreported above and thus reported as a single retention time.

TABLE A Observed Example LC/MS or No. Structure HPLC data ZZ-1

ES⁺ MS: 419 (M + 1) ZZ-2

ES⁺ MS: 406 (M + 1) ZZ-3

ES⁺ MS: 509 (M + 1) ZZ-4

ES⁺ MS: 429 (M + 1) ZZ-5

ES⁺ MS: 415 (M + 1) ZZ-6

ES⁺ MS: 491 (M + 1) ZZ-7

ES⁺ MS: 509 (M + 1) ZZ-8

ES⁺ MS: 443 (M + 1) ZZ-9

ES⁺ MS: 461 (M + 1) ZZ-10

ES⁺ MS: 501 (M + 1) ZZ-11

ES⁺ MS: 475 (M + 1) ZZ-12

ES⁺ MS: 489 (M + 1) ZZ-13

ES⁺ MS: 460 (M + 1) ZZ-14

ES⁺ MS: 442 (M + 1) ZZ-15

ES⁺ MS: 489 (M + 1) ZZ-16

8.174 & 8.295 min. ZZ-17

ES⁺ MS: 461 (M + 1) ZZ-18

ES⁺ MS: 447 (M + 1) ZZ-19

ES⁺ MS: 446 (M + 1) ZZ-20

ES⁺ MS: 432 (M + 1) ZZ-21

7.368 min ZZ-22

7.150 min ZZ-23

ES⁺ MS: 447 (M + 1) ZZ-24

ES⁺ MS: 447 (M + 1)

The present invention further includes the following compounds.

TABLE B No (R) m R^(a) 1 4-F —CH₃ 2 4-F —CH(CH₃)₂ 3 4-F —CH₂CH₂OCH₃ 42,4-F —CH₃ 5 2,4-F —CH(CH₃)₂ 6 2,4-F —CH₂CH₂OCH₃ 7 2-F,3-Cl —CH₃ 82-F,3-Cl —CH(CH₃)₂ 9 2-F,3-Cl —CH₂OH₂OCH₃

Experimental Example 1

The HIV integrase inhibitory activity was investigated based on thefollowing assay method.

(1) Preparation of DNA Solution

By the same method as that described in Experimental Example 1 of WO2004/024693, a substrate DNA solution (2 pmol/μl) and a target DNAsolution (5 pmol/μl) were prepared, After each target DNA solution wasonce boiled, a temperature was slowly lowered to anneal complementarychains, which was used. Each sequence of a substrata DNA and a targetDNA is as described in the same Experimental Example.

(2) Measurement of Inhibition Rate (IC₅₀ Value)

Streptavidin (manufactured by Vector Laboratories) was dissolved in a0.1M carbonate buffer solution (composition: 90 mM Na₂CO₃, 10 mM NaHCO₃)to a concentration of 40 μg/ml, Each 50 μl of this solution was added toa well of an immunoplate (manufactured by NUNC), this is allowed tostand at 4° C. overnight to adsorb. Then, each well was washed with aphosphate buffer (composition: 13.7 mM NaCl, 0.27 mM KCl, 0.43 mMNa₂HPO₄, 0.14 mM KH₂PO₄) two times, and 300 μl of a phosphate buffercontaining 1% skim milk to block it for 30 minutes. Further, each wellwas washed with a phosphate buffer two times, 50 μl of a substrate DNAsolution (2 pmol/μl) was added to adsorb at room temperature for 30minutes while shaking, and this was washed with a phosphate buffer twotimes and, then, distilled water once.

Then, to each well prepared as described above were added 12 μl of abuffer (composition: 150 mM MOPS (pH7.2), 75 mM MuCl₂, 50 mM2-mercaptoethanol, 25% glycerol, 500 μg/ml bovine serum albumin-fractionV), and 51 μl of a reaction solution prepared from 39 μl of distilledwater. Then, 9 μl of an integrase solution (30 pmol) was added, and themixture was mixed well. To a well as a negative control (NC) was added 9μl of a diluting solution (composition: 20 mM MOPS (pH7.2), 400 mMpotassium glutamate, 1 mM EDTA, 0.1% NP-40, 20% glycerol, 1 mM DTT, 4 Murea), and this was mixed well using a plate mixer.

After the plate was incubated at 30° C. for 60 minutes, the reactionsolution was discarded, followed by washing with 250 μl of a washingbuffer (composition: 150 mM MOPS (pH7.2), 50 mM 2-mercaptoethanol, 25%glycerol, 500 μg/ml bovine serum albumin-fraction V) three times.

Then, to each well were added 12 μl of a buffer (composition: 150 mMMOPS (pH7.2), 75 mM MgCl₂, 50 mM 2-mercaptoethanol, 25% glycerol, 500μg/ml bovine serum albumin-fraction V), and 53 μl of a reaction solutionprepared from 41 μl of distilled water. Further, 6 μl of a solution of atest compound in DMSO was added to each well, and 6 μl of DMSO was addedto a well as a positive control (PC), followed by mixing well using aplate mixer. After the plate was incubated at 30° C. for 30 minutes, 1μl of a target DNA (5 pmol/μl) was added, and this was mixed well usinga plate mixer.

After each plate was incubated at 30° C. for 10 minutes, the reactionsolution was discarded, followed by washing with a phosphate buffer twotimes. Then, an anti-digoxigenin antibody labeled with alkalinephosphatase (sheep Fab fragment: manufactured by Boehringer) was diluted2000-fold with an antibody diluting solution, 100 μl of the diluent wasadded to bind at 30° C. for 1 hour, and this was washed successivelywith a phosphate buffer containing 0.06% Tween20 two times, and aphosphate buffer once. Then, 150 μl of an alkaline phosphatase coloringbuffer (composition: 10 mM paranitrophenyl phosphate (manufactured byVector Laboratories), 5 mM MgCl₂, 100 mM NaCl, 100 mM Tris-HCl (pH 9.5))was added to react at 30° C. for 2 hours, 50 μl of a 1N NaOH solutionwas added to stop the reaction, an absorbance (OD405 nm) of each wellwas measured, and an inhibition rate (IC₅₀) was obtained according tothe following calculation equation.

Inhibition rate (%)=100[1−{(Cabs.−NCabs.)/(PCabs.−NCabs.)}]

C abs.: absorbance of well of compound

NC abs.: absorbance of NC

PC abs.: absorbance of PC

Results are shown below.

TABLE 1 Integrase inhibitory activity Example No. (IC50, ng/ml) C-2 3.3F-2 3.8 H-2 3.2

The present compound showed the strong integrase inhibitory activityagainst HIV.

Experimental Example 2

A derivative of 293T cells expressing an attachment factor to improveadherence to plastic were used for the assay. A VSV-g pseudotyped HIVvector that expresses luciferase (herein referred to as PHIV) wasproduced by transfection of cells with the pGJ3-Luci vector plasmid(Jármy, G. et al., J. Medical Virology, 64:223-231, 2001) and pVSV-g(Clontech). Cells were mixed with the PHIV vector and then mixed withserially diluted compounds. After incubation at 37° C. and 5% CO₂ fortwo days, the plates were read by using Steady Glo luciferase assayreagent (Promega) as recommended by the manufacturer. To assess non-HIVspecific inhibition, a similar assay was performed, except thatcell/PHIV vector mixture was replaced by cells which had been previouslytransduced and constitutively expressed luciferase.

TABLE 2 PHIV IC₅₀ * = <10 nM, Example ** = 10-100 nM, number *** >100 nMZ-1 * Z-2 * Z-3 * Z-4 * Z-5 * Z-6 * Z-7 * Z-8 ** Z-9 * Z-10 * Z-11 *Z-12 * Z-13 ** Z-14 ** Z-15 * Z-16 * Z-17 * Z-18 * Z-19 * Z-20 ** Z-21 *Z-22 * Z-23 * Z-24 * Z-25 * Z-26 * Z-27 *** Z-28 * Z-29 * Z-30 * Z-31 *Z-32 * Z-33 * Z-34 * Z-35 * Z-36 * Z-37 * Z-38 ** Z-39 * Z-40 * Z-41 *Z-42 * Z-43 * Z-44 * Z-45 * Z-46 * Z-47 * Z-48 * Z-49 * Z-50 * Z-51 *Z-52 * Z-53 * Z-54 * Z-55 ** Z-59 * Z-60 *

Formulation Example

A term “active ingredient” means the present compound, a tautomerthereof, a pharmaceutically acceptable thereof, or a solvate thereof.

Formulation Example 1

A hard gelatin capsule is prepared using the following ingredients:

dose (mg/capsule) Active ingredient 250 Starch (dried) 200 Magnesiumstearate 10 Total 460 mg

Formulation Example 2

A tablet is prepared using the following ingredients:

dose (mg/tablet) Active ingredient 250 Cellulose (microcrystalline) 400Silicon dioxide (fumed) 10 Stearic acid 5 Total 665 mg

Ingredients are mixed, and compressed to obtain tablets, each weighing665 mg.

1-56. (canceled)
 57. A compound of Formula (XXVI):

wherein: R¹ is hydrogen or lower alkyl; R² is optionally substitutedphenyl; R³ is hydrogen, halogen, hydroxy, optionally substituted loweralkyl, optionally substituted cycloalkyl, optionally substituted loweralkenyl, optionally substituted lower alkoxy, optionally substitutedlower alkenyloxy, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted heterocyclyl, optionally substitutedheterocyclyloxy or optionally substituted amino, wherein the optionalsubstituents are 1 to 4 substituents selected from the group consistingof hydroxy, carboxy, halogen, halo lower alkyl, halo lower alkoxy, loweralkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, loweralkoxy, lower alkenyloxy, lower alkoxycarbonyl, nitro, nitroso, amino,alkylamino, acylamino, aralkylamino, aryl, aralkyl, cyano, isocyano,isocyanate, thiocyanate, isothiocyanate, mercapto, alkylthio,alkylsulfonyl, alkylsulfonylamino, carbamoyl, alkylcarbamoyl, sulfamoyl,acyl, formyloxy, haloformyl, oxal, thioformyl, thiocarboxy,dithiocarboxy, thiocarbamoyl, sulfino, sulfo, sulfoamino, hydrazino,azido, ureido, guanidino, phthalimide, oxo, phosphoric acid, lower alkylwhich is substituted with phosphoric acid and may be intervened with aheteroatom, aryl substituted with phosphoric acid, aralkyl substitutedwith phosphoric acid, and hydroxy lower alkyl; X is lower alkylene; n is1, 2 or 3; R¹⁵ to R¹⁸ are each independently hydrogen, C₁-C₈alkyl,C₆-C₁₄arylC₁-C₈alkyl, C₆-C₁₄aryl, or alkoxy or any combination of (R¹⁵and R¹⁶), (R¹⁷ and R¹⁸), or (R¹⁶ and R¹⁸), taken together with theneighboring atom(s), form an optionally substituted 5- to 6-memberedcarbocycle or an optionally substituted 5- to 6-membered heterocycle; ora pharmaceutically acceptable salt thereof.
 58. The compound accordingto claim 57, or pharmaceutically acceptable salt thereof, wherein R¹⁵ toR¹⁸ are each independently hydrogen, C₁-C₈alkyl, C₆-C₁₄arylC₁-C₈alkyl,C₆-C₁₄aryl, or alkoxy.
 59. The compound according to claim 58, or apharmaceutically acceptable salt thereof, wherein n is
 1. 60. Thecompound according to claim 58, or a pharmaceutically acceptable saltthereof, wherein n is
 2. 61. The compound according to claim 58, or apharmaceutically acceptable salt thereof, wherein n is
 3. 62. Thecompound according to claim 57, or a pharmaceutically acceptable saltthereof, wherein a combination of (R¹⁵ and R⁶), (R¹⁷ and R¹⁸), or (R¹⁶and R¹⁸), taken together with the neighboring atom(s), form anoptionally substituted 5- to 6-membered carbocycle or an optionallysubstituted 5- to 6-membered heterocycle.
 63. The compound according toclaim 62, or a pharmaceutically acceptable salt thereof, wherein n is 1.64. The compound according to claim 62, or a pharmaceutically acceptablesalt thereof, wherein n is
 2. 65. The compound according to claim 62, ora pharmaceutically acceptable salt thereof, wherein n is
 3. 66. Apharmaceutical composition comprising the compound according to claim57, or a pharmaceutically acceptable salt thereof.
 67. Thepharmaceutical composition according to claim 66, wherein saidcomposition comprises at least one additional therapeutic agent selectedfrom reverse transcriptase inhibitors and protease inhibitors.
 68. Aprocess for the preparation of the compound according to claim 57, or apharmaceutically acceptable salt thereof, comprising the step ofdeprotecting a compound of formula (XXV):

Wherein P¹ is a hydroxyl protecting group, to form the compound ofFormula (XXVI) according to claim 1, or a pharmaceutically acceptablesalt thereof.
 69. A process for the preparation of the compoundaccording to claim 57, or a pharmaceutically acceptable salt thereof,comprising the step of reacting a compound of Formula (XVI):

wherein P¹ is a hydroxy protecting group and P³ is a carboxy protectinggroup, with an amine of Formula (XXIV):

to form a compound of Formula (XXV):